US20140179670A1 - Uracil derivative and use thereof for medical purposes - Google Patents

Uracil derivative and use thereof for medical purposes Download PDF

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US20140179670A1
US20140179670A1 US14/236,571 US201214236571A US2014179670A1 US 20140179670 A1 US20140179670 A1 US 20140179670A1 US 201214236571 A US201214236571 A US 201214236571A US 2014179670 A1 US2014179670 A1 US 2014179670A1
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hydroxy
optionally substituted
halogen
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Tomoya Shiro
Masanori Tobe
Katsumi Kubota
Yosuke Takanashi
Tomoaki Nakamura
Toshihiko Sone
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Definitions

  • the present invention provides a novel uracil derivative useful as medicament showing an elastase inhibitory activity. More specifically, the present invention provides a novel uracil derivative useful as a prophylactic agent and/or a therapeutic agent for various diseases associated with elastase such as inflammatory disease.
  • Human neutrophil elastase (hereinafter, sometimes referred to as solely “elastase”) is one kind of serine protease having a molecular weight of about 30 KDa and is stored in azurophilic granules of neutrophil.
  • elastase takes, inside of neutrophils, a role for rapid digestion or degradation of phagocytized bacteria or exogenous materials, and takes, outside of neutrophils, roles for degradation of elastin, collagen (type III, type IV), proteoglycan, fibronectin which constitute interstitium of biological connective tissues such as lung, cartilage, blood vessel wall and skin, and for maintenance of tissue homeostasis.
  • Non-Patent Literature-1 In vivo, endogenous elastase-inhibiting proteins are existed. Among them, best known one is ⁇ 1-antitrypsin ( ⁇ 1-AT), and patients with genetic defect of ⁇ 1-AT are known to present chronic obstructive pulmonary disease (COPD) like-symptoms (see Non-Patent Literature-1).
  • COPD chronic obstructive pulmonary disease
  • the diseases in which elastase is suggested to associate with pathological conditions include, for example, chronic obstructive pulmonary disease (COPD), pulmonary cystic fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic interstitial pneumonia (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplantation, premature rupture of membrane, bullosa, shock, sepsis, systemic lupus erythematodes (SLE), Crohn disease, disseminated intravascular coagulation (DIC), ischemia-reperfusion induced-tissue injury, corneal scar tissue formation, mye
  • Patent Literature-1 discloses 2-pyridone derivatives as neutrophil elastase inhibitor.
  • A-1) the compounds represented by the following general formula (A-1) (corresponding to formula I of said publication document) are described.
  • X represents O . . . ;
  • Y 1 represents N . . . ; and when R 1 represents OH, Y 1 may also, in the tautomeric form, represent NR 6 ;
  • Y 2 represents CR 3 ;
  • R 1 represents . . . , when Y 1 represents N, R 1 may also represent OH;
  • the formula (A-1) can be replaced by the following formula (A-2).
  • the compounds containing uracil backbone they are clearly different in structure from the present compounds below-mentioned.
  • ring A represents a 5-membered mono-ring hetero ring which contains 1 to 3 atom(s) selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as a hetero atom, and which may have a further substituent(s);
  • ring B represents an optionally substituted hetero ring containing at least one nitrogen atom
  • ring D represents an optionally substituted cyclic group
  • ring E represents an optionally substituted cyclic group
  • R 1 represents a substituent which contains nitrogen atom(s) having basicity] (see Patent Literature-2);
  • ring A represents a 5-membered mono-ring hetero ring which contains 1 to 3 atom(s) selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and which may have a further substituent(s);
  • ring B represents a hetero ring which may be substituted and may contain 1 to 3 atom(s) selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom in addition to the described nitrogen atom;
  • ring D represents a ring group which may be substituted
  • ring E represents an optionally substituted cyclic group
  • R 1 represents a neutral group or an acidic group which contains an oxygen atom(s) and/or a sulfur atom(s)] (see Patent Literature-3).
  • a position of a substituent R 1 that is substituted on five membered ring A is a 4 th -position counting sequentially from the position binding to ring B, then ring D, while in the present compounds, ring A (corresponding to L of formula (I) described herein) is unsubstituted and a position of a substituent on ring A (corresponding to L of formula (I) described herein) is a 5 th -position, which are different each other in structure.
  • An object of the present invention is to provide a therapeutic agent for various inflammatory diseases associated with elastase.
  • uracil derivatives represented by the following formula (I) (hereinafter, sometimes referred to as “Present compound”) is provided.
  • R 1 represents a hydrogen atom, a C 1-10 alkyl group, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group and said alkene group for R 1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R 1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 2 represents a hydrogen atom, a halogen atom, a cyano group, a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ),
  • Ar 1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O) R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • L represents a six membered aromatic ring group optionally containing one to four nitrogen atoms, a Pyr-1 group of the following formula, a Tri-1 group of the following formula or an Imi-1 group of the following formula:
  • the bond 1 represents a binding to uracil ring
  • the bond 2 represents a binding to Ar 2
  • the Z 1 , Z 2 and Z 3 represents independently of each other a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a nitro group, a hydroxy group, a —NR c R d group, a —NR a C( ⁇ O)R b group, a hydrogen atom, a C 1-6 alkyl group or a C 2-6 alkene group, and said alkyl group and said alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ),
  • L when L represents a six membered aromatic ring group, the L may be optionally substituted at substitutable positions with halogen, —C( ⁇ O)NR c R d , —C( ⁇ O)OR a , hydroxy, —NR c R d , nitro, —NR a C( ⁇ O)R b , C 1-6 alkyl or C 2-6 alkene, and said alkyl and said alkene may independently of each other be optionally substituted with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ,
  • Ar 2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or more substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O) R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • R a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted with hydroxy or halogen
  • R b represents a hydrogen atom, a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a benzyl group optionally substituted with methoxy or nitro, or a C 3-6 cycloalkyl group optionally substituted with hydroxy or halogen,
  • R c and R d represents independently of each other a hydrogen atom, or a C 1-3 alkyl group optionally substituted with hydroxy or halogen, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl, hydroxy, halogen or oxo),
  • R e represents
  • a hydrogen atom a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C 1-3 alkoxy or —NR c R d ), a C 1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen), a —C( ⁇ O)NR c R d group or a —S( ⁇ O) m R b group,
  • R f represents
  • a hydrogen atom, a hydroxy group, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), a C 1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group), an -A group or a —NR a R i group,
  • R g represents
  • a hydroxy group a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group or a —NR a R i group,
  • R h represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen
  • R i represents
  • a hydrogen atom a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy, C 3-6 cycloalkyl or —NR c R d ), an -A group, a —C( ⁇ O)R b group, a —C( ⁇ O)A group or a C 1-6 alkyl carbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C 1-3 alkoxy or —NR c R d ),
  • A represents
  • aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S
  • aromatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group or —NR c R d group) or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group,
  • n an integer of one (1) or two (2)
  • n an integer of zero (0) to two (2)].
  • R 1 represents a hydrogen atom, a C 1-10 alkyl group, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group and said alkene group for R 1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R 1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 2 represents a hydrogen atom, a halogen atom, a cyano group, a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ),
  • Ar 1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one or multiple substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • L represents a six-membered aromatic ring group optionally containing one to four nitrogen atoms, a Pyr-1 group of the following formula, a Tri-1 group of the following formula or an Imi-1 group of the following formula:
  • the bond 1 represents a binding to uracil ring
  • the bond 2 represents a binding to Ar 2
  • the Z 1 , Z 2 and Z 3 represent independently of each other a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a nitro group, a hydroxy group, a —NR c R d group, a —NR a C( ⁇ O)R b group, a hydrogen atom, a C 1-6 alkyl group or a C 2-6 alkene group, and said alkyl group and said alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ),
  • L when L represents a six-membered aromatic ring group, the L may be optionally substituted at substitutable positions with halogen, —C( ⁇ O)NR c R d , —C( ⁇ O)OR a , hydroxy, —NR c R d , nitro, —NR a C( ⁇ O)R b , C 1-6 alkyl group or C 2-6 alkene group, and said alkyl group and said alkene group may independently of each other be optionally substituted at substitutable positions with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ;
  • Ar 2 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one or multiple substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • R a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted with hydroxy or halogen
  • R b represents a hydrogen atom, a C 1-6 alkyl group optionally substituted with hydroxy or halogen or a benzyl group optionally substituted with methoxy or nitro,
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group optionally substituted with hydroxy or halogen, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl, hydroxy or halogen),
  • R e represents
  • a hydrogen atom a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C 1-3 alkoxy or —NR c R d ), a C 1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen), a —C( ⁇ O)NR c R d group or a —S( ⁇ O) m R b group,
  • R f represents
  • a hydrogen atom, a hydroxy group, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), a C 1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group), an -A group or a —NR a R i group,
  • R g represents
  • a hydroxy group a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group or a —NR a R i group,
  • R h represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen
  • R i represents
  • a hydrogen atom a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group, a —C( ⁇ O)A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C 1-3 alkoxy or —NR c R d ),
  • A represents
  • aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S
  • aromatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group or —NR c R d group) or a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group, —NR
  • n an integer of 1 or 2
  • n an integer of zero (0) to two (2).
  • R 1 represents a C 1-10 alkyl group (said alkyl group may be optionally substituted with one or multiple substituents described in Substituent List 3), a C 2-6 alkene group (said alkene group may be optionally substituted with one or multiple substituents described in Substituent List 3) or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted with one or multiple substituents described in Substituent List 4).
  • R 2 represents a hydrogen atom, a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ).
  • Ar 1 represents a benzene ring or a pyridine ring
  • said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group.
  • Ar 1 represents an Ar 1 -1 group of the following formula:
  • K 1 , K 2 , K 3 and K 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and
  • X represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group;
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K 1 to K 4 with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group.
  • Ar 2 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group.
  • Ar 2 represents an Ar 2 -1 group of the following formula:
  • L 1 , L 2 , L 3 and L 4 represents all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and
  • Y represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L 1 to L 4 with C 1-6 alkyl group optionally substituted with hydroxy or halogen, or C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group).
  • L represents a benzene ring or a pyridine ring, and the position on which said benzene ring and said pyridine ring are attached to the uracil ring is an or to position to the position on which said benzene ring and the pyridine ring are attached to the Ar 2 ;
  • said benzene ring and the pyridine ring may independently of each other be optionally substituted with C 1-6 alkyl group optionally substituted with one or multiple substituents selected from the group consisting of halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d and —C( ⁇ O)OR a , halogen atom, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —NR c R d group, nitro group or —NR a C( ⁇ O)R b group).
  • R 1 represents a C 1-10 alkyl group optionally substituted at substitutable positions with one or multiple substituents described in Substituent List 3, or a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S that may be optionally substituted at substitutable positions with one or multiple substituents described in Substituent List 4.
  • R 1 represents a C 1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 1 represents a C 1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
  • R 1 represents a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S that may be optionally substituted at substitutable positions with one or multiple substituents described in Substituent List 4.
  • R 1 represents a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 1 represents a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S that may be optionally substituted with one or multiple substituents described in Substituent List 7, and said aliphatic ring group represents C 3-6 saturated carbocycle, aziridine, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, morpholine or piperazine.
  • R a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted with hydroxy or fluorine
  • R b represents a C 1-6 alkyl group optionally substituted with hydroxy or fluorine
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group optionally substituted with hydroxy or fluorine, or alternatively combine each other together with N (nitrogen atom) to which they are attached and optionally together with further O (oxygen atom) to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine),
  • R e represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, fluorine, C 1-3 alkoxy or —NR c R d ), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, fluorine, cyano, C 1-3 alkoxy or —NR c R d ), a —C( ⁇ O)NR c R d group or a —S( ⁇ O) m R b group,
  • R f represents a hydroxy group, a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, fluorine or —NR c R d ) or a —NR a R d group,
  • R g represents a hydroxy group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, fluorine or —NR c R d ) or a —NR a R i group,
  • R h represents a C 1-3 alkyl group optionally substituted with hydroxy or fluorine
  • R i represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with fluorine or —NR c R d ), an -A group, a —C( ⁇ O)-A group or a C 1-6 alkyl carbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with fluorine or —NR c R d ),
  • A represents
  • aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group or —NR c R d group) or an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group
  • n 1 or 2.
  • L represents a benzene ring (wherein, the position on which said benzene ring is attached to the uracil ring is an orto position to the position on which said benzene ring is attached to the Ar 2 , and said benzene ring may be optionally substituted at substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, —C( ⁇ O)NR c R d group or —C( ⁇ O)OH group), or a group of Pyr-1 or Tri-1 of the following formula:
  • the bond 1 represents a binding to uracil ring
  • the bond 2 represents a binding to Ar 2
  • the Z 1 and Z 2 represent independently of each other a C 1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group, a —NR c R d group, —C( ⁇ O)NR c R d or —C( ⁇ O)OH group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OH group, a —NR c R d group or a hydrogen atom),
  • R 1 represents
  • a C 1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
  • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, —C( ⁇ O)OR b group, —C( ⁇ O)NR c R d group, —C( ⁇ O)R b group or oxo group
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, —C( ⁇ O)OR b group, —C( ⁇ O)NR c R d group, —C( ⁇ O)
  • aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 2 represents a halogen atom, a —NR c R d group, or a C 1-3 alkyl group optionally substituted with —OR a or —OC( ⁇ O)R a ,
  • X represents a C 1-3 alkyl group optionally substituted with one or multiple fluorine atoms or a nitro group
  • Y represents a cyano group, a chlorine atom or a nitro group
  • R a represents a hydrogen atom, or a C 1-3 alkyl group optionally substituted with hydroxy or fluorine,
  • R b represents a C 1-3 alkyl group optionally substituted with one to three fluorine atoms
  • R c and R d represent independently of each other a C 1-3 alkyl group optionally substituted with fluorine or a hydrogen atom, or alternatively combine each other together with N to which they are attached to represent pyrrolidine or piperidine,
  • R e represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with fluorine or —NR c R d ), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with fluorine or —NR c R d ) or a —S( ⁇ O) 2 R b group,
  • R f represents a hydroxy group or a —NR a R i group
  • R g represents a C 1-3 alkyl group
  • R h represents a C 1-3 alkyl group optionally substituted with fluorine
  • R i represents a C 1-3 alkyl group (said alkyl group may be optionally substituted with fluorine or —NR c R d ) or an -A group,
  • A represents an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group, —NR c R d group or oxo group) and
  • R 1 represents a hydrogen atom, a C 1-10 alkyl group, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group and said alkene group for R 1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R 1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 2 represents a hydrogen atom, a halogen atom, a cyano group, a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ),
  • Ar 1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O) R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • L represents a six membered aromatic ring group optionally containing one to four nitrogen atoms, a Pyr-1 group of the following formula, a Tri-1 group of the following formula or an Imi-1 group of the following formula:
  • the bond 1 represents a binding to uracil ring
  • the bond 2 represents a binding to Ar 2
  • the Z 1 , Z 2 and Z 3 represent independently of each other a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a —CHO group, a nitro group, a hydroxy group, a —NR c R d group, a —NR a C( ⁇ O)R h group, a hydrogen atom, a —S( ⁇ O) m NR c2 R d2 group, a —S( ⁇ O) m NR a C( ⁇ O)R b3 group, a —S( ⁇ O) m NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇
  • L when L represents a six-membered aromatic ring group, the L may be optionally substituted at substitutable positions with halogen, —C( ⁇ O)NR c R d , —C( ⁇ O)OR a , hydroxy, —NR c R d , nitro, —NR a C( ⁇ O)R b , C 1-6 alkyl or C 2-6 alkene, and said alkyl and said alkene may independently of each other be optionally substituted with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ,
  • Ar 2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or more substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • R a represents a hydrogen atom or a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen),
  • R b represents a hydrogen atom, a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a benzyl group optionally substituted with methoxy or nitro, or a C 3-6 cycloalkyl group optionally substituted with hydroxy or halogen,
  • R b2 represents a hydrogen atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b or halogen), a benzyl group (said benzyl group may be optionally substituted with methoxy or nitro) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen),
  • R b3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen),
  • R b4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen), a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen) or an 2-isopropyl-5-methylcyclohexyl,
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group optionally substituted with C 1-3 alkoxy, cyano, hydroxy or halogen, or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b , —NR a C( ⁇ O)OR h or —NR a C( ⁇ O)R h ), C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O) R h group, —C( ⁇ O)OR
  • R c2 and R d2 represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NR a R b group, —NR a (C ⁇ O)OR h group, —NR a C( ⁇ O)R h group, C 1-3 alkoxy group, cyano group, hydroxy group or halogen atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group, C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O
  • R e represents
  • a hydrogen atom a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl may be optionally substituted with hydroxy, halogen, cyano, C 1-3 alkoxy or —NR c R d ), a C 1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen), a —C( ⁇ O)NR c R d group or a —S( ⁇ O) m R b group,
  • R f represents
  • a hydrogen atom, a hydroxy group, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), a C 1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group), an -A group or a —NR a R i group,
  • R g represents
  • hydroxy group a chlorine atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ), an -A group or a —NR a R i group,
  • R g2 represents
  • hydroxy group a chlorine atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or —NR c R d ) or an -A group,
  • R g3 represents
  • a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy or NR c R d ) or an -A group,
  • R b represents a C 1-6 alkyl optionally substituted with hydroxy or halogen
  • R i represents
  • a hydrogen atom a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C 1-3 alkoxy, C 3-6 cycloalkyl or —NR c R d ), an -A group, a —C( ⁇ O)R h group, a —C( ⁇ O)A group or a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C 1-3 alkoxy or —NR c R d ),
  • A represents
  • a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S
  • aromatic group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group or —NR c R d group)
  • a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group,
  • n an integer of 1 or 2
  • n an integer of 0 to 2].
  • the bond 1 represents a binding to uracil ring
  • the bond 2 represents a binding to Ar 2
  • the Z 1 and Z 2 represent independently of each other a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a —CHO group, a nitro group, a hydroxy group, a —NR c R d group, a —NR a C( ⁇ O)R h group, a hydrogen atom, a —S( ⁇ O) m NR c2 R d2 group, a —S( ⁇ O) m NR a C( ⁇ O)R b3 group, a —S( ⁇ O) m NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇ O) m
  • Z 1 and Z 2 represent independently of each other a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a —CHO group, a nitro group, a —NR a C( ⁇ O)R b group, a hydrogen atom, a —S( ⁇ O) m NR c2 R d2 group, a —S( ⁇ O) m NR a C( ⁇ O)R b3 group, a —S( ⁇ O) m NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇ O) m R g2 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (
  • Ar 1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group), and
  • Ar 2 represent a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are substituted independently of each other at one to three substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group).
  • Ar 1 represents the following formula of Ar 1 -1:
  • K 1 , K 2 , K 3 and K 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring
  • X represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O) R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K 1 to K 4 with further C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group),
  • Ar 2 represents the following formula Ar 2 -1:
  • L 1 , L 2 , L 3 and L 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring
  • Y represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L 1 to L 4 with further C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group).
  • R 2 represents a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ).
  • R a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted with hydroxy or halogen
  • R b represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen
  • R b2 represents a hydrogen atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b or fluorine) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine),
  • R b3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine or chlorine), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine),
  • R b4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine or chlorine), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine) or an 2-isopropyl-5-methylcyclohexyl,
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with C 1-3 alkoxy, cyano, hydroxy or fluorine), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b , —NR a C( ⁇ O)OR h or —NR a C( ⁇ O)R h ), C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR a group, —NR a C( ⁇ O)R a group, —C(
  • R c2 an R d2 represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NR a R b group, —NR a (C ⁇ O)OR h group, —NR a C( ⁇ O)R h group, C 1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl, C 1-3 alkoxy, —NR a R b , —NR a C( ⁇ O)OR h , —NR a C( ⁇ O) R h ,
  • R e represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), an -A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy or fluorine) or a —S( ⁇ O) 2 R b group,
  • R f represents a hydroxy group, an -A group or an —NR a R i group,
  • R g represents a hydroxy group, a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, fluorine or —NR c R d ), a chlorine atom, an -A group or a —NR a R i group,
  • R g2 represents a hydroxy group, a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), a chlorine atom or an -A group,
  • R g3 represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, fluorine or —NR c R d ),
  • R h represents a C 1-3 alkyl group optionally substituted with hydroxy or fluorine
  • R i represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, C 1-3 alkoxy or fluorine) or an -A group,
  • A represents
  • aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine) or an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl, C 1-3 alkoxy, hydroxy, fluorine, —NR c R d or oxo), and
  • n an integer of 1 or 2.
  • R 1 represents a C 1-10 alkyl group (said alkyl group may be substituted at substitutable positions with one to three substituents selected from the group consisting of
  • aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 1 represents
  • a C 1-10 alkyl group (said alkyl group may be substituted at substitutable positions with one to three substituents selected from the group consisting of
  • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy, halogen, —C( ⁇ O)OR b , —C( ⁇ O)NR c R d , —C( ⁇ O)R b or oxo group)
  • aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • Z 1 represents a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a hydrogen atom, a —S( ⁇ O) 2 NR c2 R d2 group, a —S( ⁇ O) 2 NR a C( ⁇ O)R b3 group, a —S( ⁇ O) 2 NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) 2 NR a C( ⁇ O)NR a R b3 group or a S( ⁇ O) 2 R g group,
  • X represents a C 1-3 alkyl group optionally substituted one or multiple fluorine atoms or a nitro group
  • Y represents a cyano group, a chlorine atom or a nitro group).
  • Z 1 represents a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a —S( ⁇ O) 2 NR c2 R d2 group, a —S( ⁇ O) 2 NR a2 C( ⁇ O)R b3 group, a —S( ⁇ O) 2 NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) 2 NR a C( ⁇ O)NR a R b3 group, a S( ⁇ O) 2 R g group, an iodine atom, a bromine atom or a chlorine atom, and
  • R 2 represents a C 1-3 alkyl group optionally substituted with hydroxy.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof as active ingredient and a pharmaceutical carrier.
  • An esterase inhibitor comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof as active ingredient.
  • An agent for treatment or prophylaxis of inflammatory diseases comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof.
  • An agent for treatment or prophylaxis of diseases required for elastase inhibitory activity comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof.
  • a pharmaceutical composition for use in treatment or prophylaxis of inflammatory diseases comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof as active ingredient.
  • a method for treatment or prophylaxis of inflammatory diseases which comprises administering a therapeutically effective amount of the compound according to any one of [1] to [36] or physiologically acceptable salts thereof into a patient in need thereof.
  • the present invention can provide compounds showing elastase inhibitory activity, and thereby can provide a therapeutic agent or a prophylactic agent for diseases associated with elastase such as inflammatory diseases.
  • the diseases in which elastase is suggested to associate with pathological conditions include, for example, chronic obstructive pulmonary disease (COPD), pulmonary cystic fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic interstitial pneumonia (IIP) including idiopathic pulmonary fibrosis (IPF), chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplantation, premature rupture of membrane,
  • physiologically acceptable salts of compounds represented by formula (I) means acid additional physiologically acceptable salts of compounds of formula (I) that contain any groups capable of forming acid addition salts in a structure thereof, or base additional physiologically acceptable salts of compounds of formula (I) that contain any groups capable of forming base addition salts in a structure thereof.
  • acid addition salts include salts with inorganic acids (such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate and phosphate); salts with organic acids (such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate and trifluoromethanesulfonate); as well as salts with amino acids (such as glutamate and aspartate).
  • inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate and phosphate
  • organic acids such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-tol
  • base addition salts include salts with alkali metal or alkaline-earth metals (such as sodium salt, potassium salt and calcium salt); salts with organic bases (such as pyridine salts and triethylamine salts); as well as salts with amino acids (such as lysine salts and arginine salts).
  • the compound of formula (I) and salts thereof may exist in forms of hydrates and/or solvates, and thus these hydrates and/or solvates may be also encompassed in the present compounds. That is to say, “Present compound” encompasses, in addition to the above-mentioned compounds of formula (I) and physiologically acceptable salts thereof, the hydrates and/or solvates thereof.
  • the compound of formula (I) may contain one or more asymmetric carbon atoms and may form geometric isomer or axial chirality (i.e., atropisomer), and can thus exist as several kinds of stereoisomers.
  • the compounds of formula (I) of the present invention encompass each of the stereoisomer, and mixtures and racemates thereof.
  • the compounds of formula (I) may be labeled with one or more isotopes (such as 3 H, 14 C, 35 S and so on).
  • the deuterium exchange product wherein any one or two or more 1 H(s) is/are exchanged to 2 H (D) in the compounds represented by formula (I) are also encompassed in the compounds represented by these general formulae respectively.
  • the number of substituents in the certain group defined by “(may be) optionally substituted” or “substituted” should not be specifically limited as long as the group can be substituted and includes, for example one to multiple. Also, when the number of the substituents is multiple, each of the substituents may be the same or different from each other.
  • said aromatic ring group may be optionally substituted at one or more substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group” means, for example, that “said aromatic ring group is substituted at substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy
  • alkyl used herein means a straight or branched saturated hydrocarbon group
  • C 1-3 alkyl means an alkyl group having 1 to 3 carbon atoms, 1 to 6 carbon atoms, or 1 to 10 carbon atoms respectively.
  • examples of “C 1-3 alkyl group” include methyl, ethyl, propyl, isopropyl and the others
  • examples of “C 1-6 alkyl group” include in addition to the above-mentioned groups, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the others
  • examples of “C 1-10 alkyl group” include in addition to the above-mentioned groups, octyl, nonyl, decyl and the others, and said alkyl may be straight or branched.
  • examples of “C 1-3 alkyl group” include methyl, ethyl, propyl and isopropyl
  • examples of “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl
  • examples of “C 1-10 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl and nonyl.
  • C 1-6 alkylthio used herein is the same as defined in the above-mentioned “C 1-6 alkyl”, and specific examples of “C 1-6 alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, tert-butylthio and the others, and preferably include methylthio and ethylthio.
  • C 1-6 alkylcarbonyl used herein is the same as defined in the above-mentioned “C 2-6 alkyl”, and specific examples of “C 1-6 alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, tert-butylcarbonyl (pivaloyl) and the others, and preferably include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl.
  • C 3-6 cycloalkyl used herein means a ring saturated or unsaturated hydrocarbon group having 3 to 6 carbon atoms, preferably means ring saturated hydrocarbon group, and include, for example, cyclopentene, cyclohexene, cyclopropane, cyclobutane, cyclopentane and cyclohexane. Preferred examples thereof include cyclopropane, cyclobutane and cyclopentane.
  • C 3-6 saturated carbocycle used herein a ring saturated hydrocarbon group having 3 to 6 carbon atoms, and include cyclopropane, cyclobutane, cyclopentane and cyclohexane. Preferred examples thereof include cyclopropane, cyclobutane and cyclopentane.
  • C 2-6 alkene group used herein means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms, and include ethene, 1-propylene, 2-propylene, isopropylene, 1-butene, 2-butene, 3-butene, 1-pentene, 2-pentene, 3-pentene, 4-pentene, 1-hexene, 2-hexene, 3-hexene, 4-hexene, 5-hexene, 2-methyl-3-butene, 2-methyl-2-pentene, 3-methyl-2-pentene and the others.
  • Preferred examples thereof include ethene, 2-propylene and 2-butene.
  • halogen atom used herein include fluorine atom, chlorine atom, bromine atom and iodine atom. Preferred examples thereof include fluorine atom, chlorine atom and bromine atom.
  • alkoxy used herein means a group wherein the alkyl group is attached to an oxygen atom, and the “alkyl” part is the same as defined in the above-mentioned “alkyl”.
  • Specific examples of the “C 1-3 alkoxy group” include methoxy, ethoxy, n-propoxy and isopropoxy
  • specific examples of the “C 1-6 alkoxy” include in addition to the above-mentioned groups, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy hexyloxy and the others.
  • Preferred examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • C 1-6 alkoxycarbonyl used herein means a group wherein the C 1-6 alkoxy group is attached to a carbonyl group, and specific examples of the “C 1-6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the others, and preferably include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S used herein means a phenyl group and a mono-ring five to six-membered aromatic heteroring group consisting of carbon atoms as well as one to three heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom.
  • Specific examples thereof include phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, pyridazinyl, triazolyl and the others.
  • Preferred examples thereof include phenyl, pyridyl, pyrazinyl and triazolyl.
  • the term “five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S” used herein means a phenyl group and a mono-ring five to six-membered aromatic heteroring group consisting of carbon atoms as well as one to four heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Specific examples thereof include in addition to the above-mentioned specific examples for “five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S”, tetrazolyl and the others. Preferred examples thereof include phenyl, pyridyl, pyrazinyl and triazolyl.
  • the “six-membered aromatic ring group optionally containing one to four nitrogen atoms” used herein means a phenyl group and a mono-ring six-membered aromatic heteroring group consisting of carbon atoms as well as one to four nitrogen atoms, and specific examples thereof include phenyl, pyridyl, pyrimidinyl, triazinyl, tetrazinyl and the others. Preferred examples thereof include phenyl and pyridyl.
  • ix-membered aromatic ring group optionally containing one to two nitrogen atoms used herein means a phenyl group and a mono-ring six-membered aromatic heteroring group consisting of carbon atoms as well as one to two nitrogen atoms, and specific examples thereof include phenyl, pyridyl and pyrimidinyl. Preferred specific examples thereof include phenyl and pyridyl.
  • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S used herein means a mono-ring saturated hydrocarbon aliphatic ring group having three to six carbon atoms, as well as a mono-ring saturated heteroaliphatic ring group containing one to two same or different atoms selected from nitrogen atom, oxygen atom and sulfur atom.
  • the above-mentioned nitrogen atom, oxygen atom and sulfur atom are all ring-constituting atoms.
  • cyclopropyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl, tetrahydrofuranyl and the others.
  • Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl and tetrahydrofuranyl.
  • four to six-membered unsaturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S used herein means a mono-ring unsaturated hydrocarbon aliphatic ring group having four to six carbon atoms, as well as a four to six-membered unsaturated heteroaliphatic ring group containing one to two same or different atoms selected from nitrogen atom, oxygen atom and sulfur atom.
  • the above-mentioned nitrogen atom, oxygen atom and sulfur atom are all ring-constituting atoms.
  • Specific examples thereof include cyclobutenyl, cyclopentenyl, cyclohexenyl, dihydropyranyl, dihydrofuranyl, pyrrolinyl, imidazolinyl, pyrazolynlyl, oxazolinyl, thiazolinyl, dihydropyridinyl, tetrahydropyridinyl and the others.
  • Preferred specific examples thereof include cyclobutenyl, cyclopentenyl, dihydropyranyl and tetrahydropyridyl.
  • N nitrogen atom
  • O and S to represent four to six-membered saturated aliphatic ring group
  • Preferred examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
  • each other together with nitrogen atom to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent four to six-membered unsaturated aliphatic ring group used herein means a formation of a four to six-membered unsaturated heteroaliphatic ring group containing one nitrogen atom and optionally containing further one to two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom.
  • Specific examples thereof include tetrahydropyridyl, dihydropyrrolyl and the others.
  • Preferred examples thereof include tetrahydropyridyl.
  • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O used herein means a mono-ring saturated hydrocarbon aliphatic ring group having three to six carbon atoms as well as a three to six-membered saturated heteroaliphatic ring group containing one to two heteroatoms selected from nitrogen atom and oxygen atom.
  • cyclopropyl examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the others.
  • Preferred examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
  • saturated aliphatic ring group substituted with alkyl group means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkyl group.
  • Specific examples thereof include dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylazetidinyl, methylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl, ethylpiperazinyl, propylmorpholinyl and the others.
  • Preferred examples thereof include dimethylcyclobutyl, dimethylcyclopentyl, methylazetidinyl, methylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl, ethylpiperazinyl, propylmorpholinyl and the others.
  • saturated aliphatic ring group substituted with alkyl group means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkyl group.
  • Specific examples thereof include methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, methyltetrahydropyridyl, ethyltetrahydropyridyl, propyltetrahydropyridyl and the others.
  • Preferred examples thereof include methylcyclopentenyl, methyltetrahydropyridyl, ethyltetrahydropyridyl and the others.
  • each other together with nitrogen atom to which they are attached and optionally together with further oxygen atom to represent four to six-membered saturated aliphatic ring group used herein means a formation of a four to six-membered saturated heteroaliphatic ring group containing one nitrogen atom and optionally containing further one or more oxygen atoms.
  • Specific examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and the others.
  • Preferred examples thereof include azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
  • alkyl group substituted with halogen atom used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atoms.
  • Preferred examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 1,1-difluoroethyl
  • alkoxy group substituted with halogen atom means the above-mentioned alkoxy group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atom.
  • Preferred examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and 1,1-difluoroethoxy.
  • alkylthio group substituted with halogen atom used herein means the above-mentioned alkylthio group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atoms. Specific examples thereof include trifluoromethylthio, 2,2,2-trifluoroethylthio, 2-fluoroethylthio, 3-fluoropropylthio, 3,3,3-trifluoropropylthio and the others. Preferred examples include trifluoromethylthio and 2,2,2-trifluoroethylthio.
  • alkylcarbonyl group substituted with halogen atom used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atoms.
  • Specific examples thereof include trifluoromethylcarbonyl, 2-fluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 3,3,3-trifluoropropylcarbonyl and the others.
  • Preferred examples thereof include trifluoromethylcarbonyl, 2-fluoroethylcarbonyl and 2,2,2-trifluoroethylcarbonyl.
  • alkoxycarbonyl group substituted with halogen atom used herein means the above-mentioned alkoxycarbonyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atom are substituted with halogen atoms.
  • Specific examples thereof include trifluoromethoxycarbonyl, 2-fluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 3,3,3-trifluoropropoxycarbonyl and the others.
  • Preferred examples thereof include trifluoromethoxycarbonyl, 2-fluoroethoxycarbonyl and 2,2,2-trifluoroethoxycarbonyl.
  • aromatic ring group substituted with halogen atom used herein means the above-mentioned aromatic ring group substituted with one to three substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and iodine atom.
  • saturated aliphatic ring group substituted with halogen atom used herein means a mono-ring saturated aliphatic ring group substituted with one to three substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and iodine atom.
  • fluorocyclopropyl difluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, chlorocyclobutyl, dichlorocyclobutyl, fluorocyclopentyl, difluorocyclopentyl, chlorocyclopentyl, fluorocyclohexyl, difluorocyclohexyl, fluoroazetidinyl, difluoroazetidinyl, difluoropyrrolidinyl, difluoropiperidinyl, difluoromorpholinyl and the others.
  • Preferred examples thereof include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, difluorocyclopentyl, difluoroazetidinyl and difluoropyrrolidinyl.
  • unsaturated aliphatic ring group substituted with halogen atom used herein means a mono-ring four to six-membered unsaturated aliphatic ring group substituted with one to three substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and iodine atom.
  • Specific examples thereof include fluorocyclobutenyl, difluorocyclobutenyl, chlorocyclobutenyl, dichlorocyclobutenyl, fluorocyclopentenyl, difluorocyclopentenyl, chlorocyclopentenyl, fluorocyclohexenyl, difluorocyclohexenyl, difluorotetrahydropyridyl and the others.
  • Preferred examples include fluorocyclobutenyl, difluorocyclobutenyl and difluorocyclopentenyl.
  • alkyl group substituted with hydroxy group means the above-mentioned alkyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 2,5-dihydroxypentyl, 3,5-dihydroxypentyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl, 2,6-dihydroxyhexyl, 3,6-
  • alkoxy group substituted with hydroxy group means the above-mentioned alkoxy group wherein one, two or more (for example, one to five, preferably one to two) hydrogen atoms are substituted with hydroxy groups.
  • Specific examples thereof include 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 1,3-dihydroxypropoxy, 2,3-dihydroxypropoxy, 2-hydroxybutoxy, 3-hydroxybutoxy, 4-hydroxybutoxy, 2,3-dihydroxybutoxy, 3,4-dihydroxybutoxy, 2,4-dihydroxybutoxy, 2-hydroxypentyloxy, 3-hydroxypentyloxy, 4-hydroxypentyloxy, 5-hydroxypentyloxy, 2,5-hydroxypentyloxy, 3,5-hydroxypentyloxy, 2-hydroxyhexyloxy, 3-hydroxyhexyloxy, 4-hydroxyhexyloxy, 5-hydroxyhexyloxy, 6-hydroxyhexyloxy, 2,6-dihydroxyhexyloxy, 3,6-dihydroxyhexyl
  • alkylthio group substituted with hydroxy group means the above-mentioned alkylthio group wherein one, two or more (for example, one to five, preferably one to two hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include 2-hydroxyethylthio, 2-hydroxy-1-propylthio, 3-hydroxy-1-propylthio, 1-hydroxy-2-propylthio and the others. Preferred examples thereof include 2-hydroxyethylthio, 3-hydroxy-1-propylthio and 1-hydroxy-2-propylthio.
  • alkylcarbonyl group substituted with hydroxy group used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to five, preferably one to two hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, hydroxyisopropylcarbonyl, hydroxybutylcarbonyl and the others. Preferred examples thereof include hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl and hydroxybutylcarbonyl.
  • alkoxycarbonyl group substituted with hydroxy group means the above-mentioned alkoxycarbonyl group wherein one, two or more (for example, one to five, preferably one to two hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxyethoxycarbonyl, hydroxypropoxycarbonyl, hydroxyisopropoxycarbonyl, hydroxybutoxycarbonyl and the others. Preferred examples thereof include hydroxyethoxycarbonyl, hydroxypropoxycarbonyl and hydroxyisopropoxycarbonyl.
  • aromatic ring group substituted with hydroxy group means the above-mentioned aromatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with hydroxy groups.
  • saturated aliphatic ring group substituted with hydroxy group used herein means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with hydroxy groups.
  • Specific examples thereof include hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, hydroxyazetidinyl, hydroxypyrrolidinyl, hydroxypiperidinyl and the others.
  • Preferred examples thereof include hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxyazetidinyl and hydroxypyrrolidinyl.
  • unsaturated aliphatic ring group substituted with hydroxy group means the above-mentioned unsaturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with hydroxy groups.
  • Specific examples thereof include hydroxycyclobutenyl, hydroxycyclopentenyl, hydroxycyclohexenyl, hydroxytetrahydropyridyl and the others.
  • Preferred examples thereof include hydroxycyclopentenyl and hydroxycyclohexenyl.
  • aromatic ring group substituted with alkyl group used herein means the above-mentioned aromatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with alkyl groups.
  • aromatic ring group substituted with cyano group used herein means the above-mentioned aromatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • alkyl group substituted with cyano group used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • Specific examples thereof include cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, cyanobutyl, cyanoisobutyl, cyanopentyl, cyanohexyl, cyanooctyl, cyanononyl, cyanodecyl and the others.
  • Preferred examples thereof include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 1-cyano-2-propyl and 4-cyanobutyl.
  • alkoxy group substituted with cyano group means the above-mentioned alkoxy group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • Specific examples thereof include cyanomethoxy, cyanoethoxy, cyanopropoxy, cyanoisopropoxy, cyanobutoxy, cyanopentyloxy, cyanohexyloxy, cyanooctyloxy, cyanononyloxy, cyanodecyloxy and the others.
  • Preferred examples thereof include cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 1-cyano-2-propoxy and 4-cyanobutoxy.
  • alkylthio group substituted with cyano group used herein means the above-mentioned alkylthio group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include 2-cyanoethylthio, 2-cyano-1-propylthio, 3-cyano-1-propylthio, 1-cyano-2-propylthio and the others. Preferred examples thereof include 2-cyanoethylthio, 3-cyano-1-propylthio and 1-cyano-2-propylthio.
  • alkylcarbonyl group substituted with cyano group used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • Specific examples thereof include cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl, cyanoisopropylcarbonyl, cyanobutylcarbonyl, cyanopentylcarbonyl, cyanohexylcarbonyl and the others.
  • Preferred examples thereof include cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl, cyanoisopropylcarbonyl and cyanobutylcarbonyl.
  • saturated aliphatic ring group substituted with cyano group means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • Specific examples thereof include cyanocyclobutyl, cyanocyclopentyl, cyanocyclohexyl, cyanopyrrolidinyl, cyanopiperidinyl, cyanopiperazinyl, cyanomorpholinyl, cyanotetrahydrofuranyl and the others.
  • Preferred examples thereof include cyanocyclobutyl, cyanocyclopentyl, cyanocyclohexyl, cyanopyrrolidinyl and cyanopiperidinyl.
  • unsaturated aliphatic ring group substituted with cyano group used herein means the above-mentioned unsaturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • Specific examples thereof include cyanocyclobutenyl, cyanocyclopentenyl, cyanocyclohexenyl, cyanodihydropyranyl, cyanodihydrofuranyl, cyanodihydropyridyl, cyanotetrahydropyridyl and the others.
  • Preferred examples thereof include cyanocyclopentenyl, cyanocyclohexenyl, cyanodihydropyridyl and cyanotetrahydropyridyl.
  • alkyl group substituted with alkoxy group used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups.
  • Specific examples thereof include methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, isopropoxypropyl, methoxyisopropyl, ethoxyisopropyl, propoxyisopropyl, isopropoxyisopropyl, methoxybutyl, ethoxybutyl, propoxybutyl, isopropoxybutyl, methoxyisobutyl, ethoxyisobutyl, propoxyisobutyl, isopropoxyisobutyl and the others.
  • Preferred examples thereof include methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl and ethoxypropyl.
  • aromatic group substituted with alkoxy group means the above-mentioned aromatic group wherein one, two or more (for example, one to three) hydrogens are substituted with the above-mentioned alkoxy groups.
  • alkylcarbonyl group substituted with alkoxy group used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups.
  • Specific examples thereof include methoxymethylcarbonyl, ethoxymethylcarbonyl, methoxyethylcarbonyl, ethoxyethylcarbonyl, methoxypropylcarbonyl, methoxyisopropylcarbonyl and the others.
  • Preferred examples thereof include methoxymethylcarbonyl, ethoxymethylcarbonyl, methoxyethylcarbonyl and ethoxyethylcarbonyl.
  • saturated aliphatic ring group substituted with alkoxy group means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups.
  • Specific examples thereof include methoxycyclopropyl, ethoxycyclopropyl, methoxycyclobutyl, ethoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl, methoxytetrahydropyranyl, methoxypyrrolidinyl, methoxypiperidinyl, methoxytetrahydrofuranyl, methoxyazetidinyl, ethoxyazetidinyl, methoxypyrrolidinyl, ethoxypyrrolidinyl, methoxypiperidinyl and the others.
  • Preferred examples thereof include methoxycyclopropyl, ethoxycyclopropyl, methoxycyclobutyl, ethoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl and methoxyazetidinyl.
  • unsaturated aliphatic ring group substituted with alkoxy group means the above-mentioned unsaturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups.
  • Specific examples thereof include methoxycyclobutenyl, methoxycyclopentenyl, methoxycyclohexenyl, ethoxycyclobutenyl, ethoxycyclopentenyl, ethoxycyclohexenyl, methoxydihydropyranyl, methoxydihydrofuranyl, methoxytetrahydropyridinyl and the others.
  • alkyl group substituted with optionally substituted aromatic ring group used herein means the above-mentioned alkyl group wherein one, two or more hydrogen atoms are substituted with “optionally substituted aromatic ring group”. Specific examples thereof include an alkyl group having one to six carbon atoms wherein any hydrogen atoms are substituted with optionally substituted aromatic ring groups such as phenyl, pyridyl, oxazolyl, thiazolyl and pyrazolyl. Specific examples of substituents of said optionally substituted aromatic ring group include methoxy, methanesulfonyl, dimethylamino, cyano and the others.
  • alkoxy group substituted with optionally substituted aromatic ring group used herein means a group wherein the above-mentioned “alkyl group substituted with optionally substituted aromatic ring group” is attached to an oxygen atom.
  • alkylthio group substituted with optionally substituted aromatic ring group used herein means a group wherein the above-mentioned alkyl group substituted with optionally substituted aromatic ring group is attached to a sulfur atom.
  • saturated aliphatic ring group substituted with oxo group means the above-mentioned saturated aliphatic ring group wherein one to two hydrogen atoms are replaced with oxo groups.
  • Specific examples thereof include 2-oxocyclopentyl, 3-oxocyclopentyl, 2-oxocyclohexyl, 3-oxocyclohexyl, 4-oxocyclohexyl, 2-oxopyrrolidinyl, 3-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, 2-oxopiperidinyl, 3-oxopiperidinyl, 4-oxopiperidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 2-oxomorpholinyl, 2-oxothiomorpholinyl, oxoimidazolidinyl, dioxoimidazolidinyl
  • unsaturated aliphatic ring group substituted with oxo group means the above-mentioned unsaturated aliphatic ring group wherein one to two oxo hydrogen atoms are replaced with oxo groups.
  • Specific examples thereof include oxocyclopentenyl, oxocyclohexenyl, oxopyrrolinyl, oxoimidazolinyl, oxo-oxazolidinyl, oxothiazolinyl, oxodihydropyridinyl, oxotetrahydropyridinyl and the others.
  • Preferred examples thereof include oxopyrrolinyl, oxoimidazolinyl, oxodihydropyridinyl and oxotetrahydropyridinyl.
  • aliphatic ring group means an alicyclic group.
  • R a represents a hydrogen atom or a C 1-6 alkyl optionally substituted with hydroxy group or halogen atom, preferably a hydrogen atom or a C 1-3 alkyl group optionally substituted with hydroxy group or fluorine atom, and more preferably a hydrogen atom, methyl, ethyl, trifluoromethyl, difluoromethyl, hydroxymethyl or hydroxyethyl.
  • R b represents a hydrogen atom, a C 1-6 alkyl optionally substituted with hydroxy group or halogen atom, a benzyl group optionally substituted with methoxy group or nitro group or a C 3-6 cycloalkyl group optionally substituted with hydroxy group or halogen atom, preferably a hydrogen atom, a C 1-6 alkyl group optionally substituted with hydroxy group or halogen atom or a benzyl group optionally substituted with methoxy group or nitro group, and more preferably a hydrogen atom or a C 1-3 alkyl group optionally substituted with hydroxy group or fluorine atom.
  • R b represents preferably a C 1-6 alkyl group optionally substituted with hydroxy group or halogen atom, more preferably a C 1-3 alkyl group optionally substituted with hydroxy group or fluorine atom.
  • R b2 represents a hydrogen atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NR a R b or halogen atom), a benzyl group (said benzyl group may be optionally substituted with methoxy group or nitro group) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or halogen atom), preferably a hydrogen atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NR a R b or fluorine atom) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom), more preferably a hydrogen atom or a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or —NR
  • R b3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen atom), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or halogen atom) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or halogen atom), preferably a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom), and more preferably a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy
  • R b4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen atom), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or halogen atom), a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or halogen atom) or an 2-isopropyl-5-methylcyclohexyl, preferably a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom) or an 2-isopropyl-5-methylcyclo
  • R c and R d represent independently of each other a hydrogen atom, or a C 1-3 alkyl group optionally substituted with an C 1-3 alkoxy group, cyano group, hydroxy group or halogen atom, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b , —NR a C( ⁇ O)OR h , or NR a C( ⁇ O)R h ), C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O)R h group, —C(
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with C 1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b , —NR a C( ⁇ O)OR h or —NR a C( ⁇ O) R h ), C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O)R
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with methoxy, cyano, hydroxy or fluorine) or alternatively combine each other to represent a saturated heteroaliphatic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine and morpholine (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NR a R b or —NR a C( ⁇ O)R h ), methoxy group, —NR a R b group, —NR a C( ⁇ O)R h group, hydroxy group, fluorine atom or oxo group).
  • R c2 and R d2 represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NR a R b group, —NR a (C ⁇ O)OR h group, —NR a C( ⁇ O)R h group, C 1-3 alkoxy group, cyano group, hydroxy group or halogen atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group, C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O)
  • R c2 and R d2 represent independently of each other to represent a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NR a R b group, —NR a (C ⁇ O)OR h group, —NR a C( ⁇ O)R h group, C 1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group, C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O)
  • R c2 and R d2 represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with —NR a R b , —NR a C( ⁇ O)R h , methoxy, cyano, hydroxy or fluorine) or alternatively combine each other to represent a saturated heteroaliphatic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, morpholine, oxazolidine and imidazolidine (said aliphatic ring group may be optionally substituted at substitutable positions with methoxy, —NR a R b , —NR a C( ⁇ O)R h , hydroxy, fluorine or oxo).
  • R e represents a hydrogen atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy group, halogen atom, cyano group, C 1-3 alkoxy group or —NR c R d group), a C 1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy group or halogen atom), —C( ⁇ O)NR c R d group or —S( ⁇ O) m R b group,
  • a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, fluorine atom, C 1-3 alkoxy group, or —NR c R d group), an -A group, a —C( ⁇ O)-A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of the alkylcarbonyl group may be optionally substituted with hydroxy group or halogen atom), a —C( ⁇ O)NR c R d group or a —S( ⁇ O) m R b group,
  • a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), an -A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy group or fluorine atom) or a —S( ⁇ O) 2 R b group.
  • R f represents a hydrogen atom, a hydroxy group, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom group, C 1-3 alkoxy group or —NR c R d group), a C 1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group), an -A group or a —NR a R i group; preferably, represents a hydrogen atom, a hydroxy group, a C 1-3 alkyl group, a C 1-3 alkoxy group, an -A group or a —NR a R i group; and more preferably, represents a hydroxy group, an -A group or a —NR a R i group.
  • R g represents a hydroxy group, a chlorine atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group), an -A group or a —NR a R i group; preferably, represents a chlorine atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group or fluorine atom), an -A group or a —NR a R i group; and more preferably, represents a C 1-3 alkyl group (said alkyl group may be optionally substituted with cyano group or fluorine atom), an -A group or a —NR a R i group.
  • R g represents preferably a hydroxy group, a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom, or —NR c R d group), a chlorine atom, an -A group or a —NR a R i group.
  • R g2 represents a hydroxy group, a chlorine atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group) or an -A group; preferably represents a hydroxy group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a chlorine atom or an -A group; and more preferably represents a hydroxy group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom).
  • R g3 represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group or —NR c R d group) or an -A group; preferably represent a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom or —NR c R d group).
  • R h represents a C 1-6 alkyl group optionally substituted with hydroxy group or halogen atom, preferably a C 1-3 alkyl group optionally substituted with hydroxy group or fluorine atom, and more preferably methyl, ethyl or trifluoroethyl.
  • R i represents a hydrogen atom or a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C 1-3 alkoxy group, C 3-6 cycloalkyl group or —NR c R d group), an -A group, a —C( ⁇ O)R b group, a —C( ⁇ O)R h group, a —C( ⁇ O)A group or a C 1-6 alkylcarbonyl group (the alkyl moiety of the alkylcarbonyl group may be optionally substituted with hydroxy group, halogen atom, cyano group, C 1-3 alkoxy group or —NR c R d group); preferably represents a hydrogen atom or a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, fluorine atom, C 1-3 alkoxy group, C 3-6 cycloalky
  • A represents a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S
  • aromatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group or —NR c R d group) or a three to six-membered saturated or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group
  • aromatic ring group preferably, represents an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (said aromatic ring group may be optionally substituted with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C( ⁇ O)OH group or —NR c R d group) or an optionally substituted saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • aromatic heteroring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl
  • aromatic heteroring group may be optionally substituted with C 1-3 alkyl group optionally substituted with hydroxy or fluorine, C 1-3 alkoxy group optionally substituted with hydroxy or fluorine, hydroxy group, fluorine atom, cyano group, —C( ⁇ O)OH group or —NR c R d group
  • a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl
  • said aliphatic ring group may be
  • aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl
  • said aliphatic ring group may be optionally substituted with C 1-3 alkyl group optionally substituted with hydroxy or fluorine, C 1-3 alkoxy group optionally substituted with hydroxy or fluorine atom, hydroxy group, fluorine atom, cyano group, —C( ⁇ O)OH group or —NR c R d group).
  • A represents an aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine), or
  • an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group, C 1-3 alkoxy group, hydroxy group, fluorine atom, —NR c R d or oxo group).
  • R a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted with hydroxy group or halogen atom
  • R b represents a C 1-6 alkyl group optionally substituted with hydroxy group or halogen atom
  • R b2 represents a hydrogen atom, a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NR a R b group or fluorine atom) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom);
  • R b3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom) or a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom);
  • R b4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a C 3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom) or a residue of menthol group;
  • R c and R d represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with C 1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to form a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, or NR a C( ⁇ O)R h group), a C 1-3 alkoxy group, a —NR a R b group, a —NR a C( ⁇ O)OR a group, a —NR
  • R c2 and R d2 represent independently of each other a hydrogen atom or a C 1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NR a R b group, —NR a (C ⁇ O)OR h group, —NR a C( ⁇ O)R h group, C 1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to form a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-6 alkyl group, C 1-3 alkoxy group, —NR a R b group, —NR a C( ⁇ O)OR h group, —NR a C( ⁇ O)R h
  • R e represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), an -A group, a C 1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy group or fluorine atom) or a —S( ⁇ O) 2 R b group;
  • R f represents a hydroxy group, an -A group or a —NR a R i group
  • R g represents a hydroxy group, a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom or —NR c R d group), a chlorine atom, an -A group or a —NR a R i group;
  • R g2 represents a hydroxy group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a chlorine atom or an -A group;
  • R g3 represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom or —NR c R d group);
  • R h represents a C 1-3 alkyl group optionally substituted with hydroxy group or fluorine tom
  • R i represents a C 1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, C 1-3 alkoxy group or fluorine atom) or an -A group;
  • A represents
  • aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy group or fluorine atom) or
  • an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group, C 1-3 alkoxy group, hydroxy group, fluorine atom, —NR c R d group or oxo group); and
  • n is an integer of 1 or 2.
  • R 1 represents a hydrogen atom, a C 1-10 alkyl group, a C 2-6 alkene group, or a three to six-membered saturated- or four- to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • alkyl group and said alkene group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • saturated or unsaturated aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 1 represents preferably a C 1-10 alkyl group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (14) of Substituent List 1,
  • said saturated or unsaturated aliphatic ring group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (20) of Substituent List 2,
  • R 1 represents more preferably a C 1-10 alkyl group or a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (4) and (6) to (10) of Substituent List 1,
  • said saturated aliphatic ring group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (4), (7) to (12), (14), (19) and (20) of Substituent List 2,
  • R 1 represents further more preferably
  • a C 1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of the followings:
  • saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted at substitutable positions with
  • saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • saturated aliphatic ring group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of the followings:
  • R 1 represents preferably
  • a C 1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
  • aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 1 represents more preferably
  • a C 1-10 alkyl group (said alkyl may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
  • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • said aliphatic ring group may be optionally substituted at substitutable positions with C 1-3 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, —C( ⁇ O)OR b group, —C( ⁇ O)NR c R d group, —C( ⁇ O)R b group or oxo group)
  • aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • R 2 represents a hydrogen atom, a halogen atom, a cyano group, a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ).
  • R 2 represents preferably a —NR c R d group, a —N ⁇ CHN(CH 3 ) 2 group or a C 2-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ).
  • R 2 represents more preferably a hydrogen atom, an amino group or a C 1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NR c R d , —OR a or —OC( ⁇ O)R a ), and represents further more preferably a hydrogen atom, an amino group, a methyl group or a hydroxymethyl group.
  • n represents an integer of one (1) or two (2) and preferably represents 2.
  • n an integer of zero (0) to two (2) and preferably represents 2.
  • L represents a six-membered aromatic ring group optionally containing one to four nitrogen atoms (said group may be optionally substituted at substitutable positions with halogen, —C( ⁇ O)NR c R d , —C( ⁇ O)OR a , hydroxy, —NR c R d , nitro, —NR a C( ⁇ O)R b , C 1-6 alkyl or C 2-6 alkene, wherein said alkyl and said alkene may be optionally substituted independently of each other with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ), a Pyr-1 of the following formula, a Tri-1 of the following formula or an Imi-1 of the following formula:
  • bond 1 represents a binding to uracil ring
  • bond 2 represents a binding to Ar 2
  • Z 1 , Z 2 and Z 3 represent independently of each other a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, —C( ⁇ O)OR b2 group, —CHO group, a nitro group, a hydroxy group, a —NR c R d group, a —NR a C( ⁇ O)R h group, a hydrogen atom, a —S( ⁇ O) m NR c2 R d2 group, a —S( ⁇ O) m NR a C( ⁇ O)R b3 group, a —S( ⁇ O) m NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇ O)OR b4 group
  • bond 1 represents a binding to uracil ring
  • bond 2 represents a binding to Ar 2
  • Z 1 , Z 2 and Z 3 may be optionally substituted independently of each other with halogen, —C( ⁇ O)NR c R d , —C( ⁇ O)OR a , nitro, hydroxy, —NR c R d , —NR a C( ⁇ O)R b , hydrogen, C 1-6 alkyl or C 2-6 alkene, wherein said alkyl and said alkene may be optionally substituted independently of each other with halogen, hydroxy, —NR c R d , —C( ⁇ O)NR c R d or —C( ⁇ O)OR a ).
  • L represents
  • a six-membered unsubstituted aromatic ring group optionally containing one to two nitrogen atoms, a Pyr-1 of the following formula or a Tri-1 of the following formula:
  • bond 1 represents a binding to uracil ring
  • bond 2 represents a binding to Ar 2
  • Z 1 and Z 2 represent independently of each other a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, —CHO group, a nitro group, a hydroxy group, a —NR c R d group, a —NR a C( ⁇ O)R h group, a hydrogen atom, a —S( ⁇ O) m NR c2 R d2 group, a —S( ⁇ O) m NR a C( ⁇ O)R b3 group, a —S( ⁇ O) m NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇ O) m R
  • Z 1 and Z 2 represent independently of each other a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a —CHO group, a nitro group, a —NR a C( ⁇ O)R b group, a hydrogen atom, a —S( ⁇ O) m NR c2 R d2 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇ O) m NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) m NR a C( ⁇ O)NR a R b3 group, a —S( ⁇ O) m R g2 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of
  • preferred binding position on said aromatic ring represents a binding manner in which said uracil backbone and said Ar 2 are attached to adjacent carbon atoms on the aromatic ring respectively as shown in the following formula (I′):
  • L represents preferably a benzene ring group, a pyridine ring group, a group of formula Pyr-1, a group of formula Tri-1 or a group of formula Imi-1, and represents more preferably a benzene ring group, a pyridine ring group, a group of formula Pyr-1 or a group of formula Tri-1. Further more preferably, L represents a group of formula Pyr-1.
  • Ar 1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or multiple substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group or —NR c R d group),
  • Ar 1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions independently of each other with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group),
  • Ar 1 represents a benzene ring or a pyridine ring represented by the following formula Ar 1 -1:
  • K 1 , K 2 , K 3 and K 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring
  • X represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K 1 to K 4 further with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group,
  • Ar 1 represents a group of the following formula Ar 1 -10:
  • X represents a C 1-3 alkyl group optionally substituted with one to three fluorine atoms, a chlorine atom, a cyano group or a nitro group).
  • Ar 2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or multiple substitutable positions with C 1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NR a C( ⁇ O)R h group, —NR a S( ⁇ O) m R h group, —NR a C( ⁇ O)NR c R d group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) m NR c R d group, —S( ⁇ O) n R h group, or —NR c R d group),
  • Ar 2 represents a benzene ring or a pyridine ring represented by the following formula Ar 2 -1:
  • L 1 , L 2 , L 3 and L 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring
  • Y represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L 1 to L 4 further with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group,
  • Ar 2 represents a structure wherein L 2 position is unsubstituted or is substituted with C 1-6 alkyl, C 1-3 alkoxy, hydroxy, halogen or —S( ⁇ O) n R h ,
  • Ar 2 represents a group of the following formula Ar 2 -10:
  • Y represents a cyano group, a chlorine atom or a nitro group
  • Ar 1 and Ar 2 include the followings:
  • Ar 1 represents the following formula Ar 1 -1:
  • K 1 , K 2 , K 3 and K 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring
  • X represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K 1 to K 4 further with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group);
  • Ar 2 represents the following formula Ar 2 -1:
  • L 1 , L 2 , L 3 and L 4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring
  • Y represents a C 1-6 alkyl group optionally substituted with hydroxy or halogen, a C 1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR a group, a —C( ⁇ O)R a group, a —S( ⁇ O) n R h group or a —NR c R d group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L 1 to L 4 further with C 1-6 alkyl group optionally substituted with hydroxy or halogen, C 1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C( ⁇ O)NR c R d group, —C( ⁇ O)OR a group, —C( ⁇ O)R a group, —S( ⁇ O) n R h group or —NR c R d group).
  • Examples of preferred compounds as uracil derivatives represented by formula (I) include the compounds wherein the formula (I) represents the following formula (I′′′):
  • Z 1 represents a cyano group, a halogen atom, a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a hydrogen atom, a —S( ⁇ O) 2 NR c2 R d2 group, a —S( ⁇ O) 2 NR a C( ⁇ O)R b3 group, a —S( ⁇ O) 2 NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) 2 NR a C( ⁇ O)NR a R b3 group or a S( ⁇ O) 2 R g group,
  • X represents a C 1-3 alkyl group optionally substituted with one or multiple fluorines or a nitro group
  • Y represents a cyano group, a chlorine atom or a nitro group
  • Z 1 represents a —C( ⁇ O)NR c R d group, a —C( ⁇ O)OR b2 group, a —S( ⁇ O) 2 NR c2 R d2 group, a —S( ⁇ O) 2 NR a2 C( ⁇ O)R b3 group, a —S( ⁇ O) 2 NR a C( ⁇ O)OR b4 group, a —S( ⁇ O) 2 NR a C( ⁇ O)NR a R b3 group, a S( ⁇ O)) 2 R g group, an iodine atom, a bromine atom or a chlorine atom, and
  • R 2 represents a C 1-3 alkyl group optionally substituted with hydroxy
  • the Present compound represented by formula (I) or physiologically acceptable salts thereof is a novel compound, and can be prepared according to the below-mentioned processes, the below-mentioned examples or equivalent processes to known processes.
  • the compounds obtained by the below-mentioned processes may form salts thereof as long as they do not afford any adverse effect to an intended reaction.
  • the compounds of formula (I) is prepared according to the below-mentioned processes.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined above, and X 1 represents halogen atoms (for example, chlorine atom, bromine atom and iodine atom) or an amino group)
  • the compound (I) can be prepared by performing a coupling reaction on the compound (IIa) with Z 1 -L-Ar 2 (wherein Z 1 is a substituent on carbon atom in L ring and represents a metal substituent (for example, boronic acid, boronate ester, organotin, zinc halide, magnesium halide, organosilicon and lithium)) according to a conventional method.
  • Z 1 is a substituent on carbon atom in L ring and represents a metal substituent (for example, boronic acid, boronate ester, organotin, zinc halide, magnesium halide, organosilicon and lithium)
  • the reaction can be achieved by performing a cross-coupling reaction on the compound (IIa) and Z 1 -L-Ar 2 in appropriate solvents or under solvent-free condition in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium), copper catalysts (typically, copper iodide), nickel catalysts (typically, nickel chloride-1,2-bis(diphenylphosphino)ethane complex), zinc reagents, iron chelating reagents and the others, optionally with an addition of phosphorus ligands (typically, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphino biphenyl).
  • palladium catalysts typically, tetrakis(triphenylphosphin)palladium
  • copper catalysts typically, copper iodide
  • nickel catalysts typically, nickel chloride-1,2-bis(diphen
  • Such coupling reactions may be carried out in the co-presence of alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example or potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali hydroxides (for example, sodium hydroxide) or metal alkoxides (for example, potassium t-butoxide) in addition to the above-mentioned reagents.
  • alkali carbonates for example, sodium carbonate, potassium carbonate or cesium carbonate
  • alkali phosphates for example or potassium phosphate
  • organic bases for example, triethylamine or diisopropylethylamine
  • alkali halides for example, lithium chloride or cesium fluoride
  • alkali hydroxides for example, sodium hydroxide
  • metal alkoxides for example,
  • the compound (I) can be prepared by converting the X 1 in compound (IIa) into coupling reactive group (for example, boronic acid group, zinc halide group, and magnesium halide group) followed by performing a coupling reaction on the resultant compounds with Z 2 -L-Ar 2 (wherein Z 2 is a substituent on carbon atom in L ring and represents a halogen atom) according to a conventional method.
  • coupling reactive group for example, boronic acid group, zinc halide group, and magnesium halide group
  • this reaction can be achieved by reacting the compound (IIa) with boron reagents (typically, bis(pinacolato)diboron reagents) and palladium catalysts (typically, tetrakis(triphenylphosphin)palladium) to prepare boron compounds, by reacting the compound (IIa) with zinc dust and alkyl magnesium reagents to prepare zinc halides, or by reacting the compound (IIa) with magnesium powder to prepare magnesium halides, respectively in appropriate solvents or under solvent-free condition, followed by performing a cross-coupling reaction on the compound (IIa) with Z 2 -L-Ar 2 in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium or bis(triphenylphosphine)palladium dichloride), copper catalysts (typically, copper iodide), nickel catalysts (typically, nickel chloride-1,2-bis(diphenyl)
  • Such coupling reactions may be carried out in the co-presence of alkali metal carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example, potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali metal hydroxides (for example, sodium hydroxide) or metal alkoxides (for example, potassium t-butoxide) in addition to the above-mentioned reagents.
  • alkali metal carbonates for example, sodium carbonate, potassium carbonate or cesium carbonate
  • alkali phosphates for example, potassium phosphate
  • organic bases for example, triethylamine or diisopropylethylamine
  • alkali halides for example, lithium chloride or cesium fluoride
  • alkali metal hydroxides for example, sodium hydroxide
  • the compound (I) can be prepared by performing a cyclization of the compound (IIa) with Ar 2 's carbohydrazides (i.e., Ar 2 —C( ⁇ O)NHNH 2 ) according to a conventional method.
  • the reaction can be achieved by reacting the compound (IIa) with Ar 2 's carbohydrazides in appropriate solvents or under solvent-free condition in the presence of N,N-dimethylformamide dimethyl acetal and acetic acid.
  • the compound (I) can be prepared, for example, according to the method described in Org. Lett. 2004, 17(6), 2969-2971 or the like or equivalent methods thereto (see Example 62).
  • the compound of Z 1 -L-Ar 2 can be prepared by replacing Z 3 in the Z 3 -L-Ar 2 (wherein Z 3 is a substituent on carbon atom in L ring and represents a halogen atom or a hydrogen atom) with various metal atoms.
  • the reaction can be carried out by reacting Z 3 -L-Ar 2 with diboron reagents (for example, bis(pinacolato)diboron reagent) in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium) or by reacting Z 3 -L-Ar 2 with alkyl lithium reagents (for example, butyl lithium) followed by reacting the resultant compounds with trialkoxy borane reagents (for example, trimethyl borate reagent), respectively in appropriate solvents or under solvent-free condition to prepare boron reagents; by reacting Z 3 -L-Ar 2 with alkyllithium reagents (for example, butyllithium) followed by reacting the resultant compounds with tin chloride reagents (for example, tributyltin chloride) in appropriate solvents or under solvent-free condition to prepare organotin reagents; by reacting Z 3 -
  • Z 1 -L-Ar 2 , Z 2 -L-Ar 2 and Z 3 -L-Ar 2 can be prepared by performing a coupling reaction in Ring L and Ring Ar 2 using commercially available starting materials according to the similar methods to those of Process A-1.
  • the compounds of Z 1 -L-Ar 2 , Z 2 -L-Ar 2 and Z 3 -L-Ar 2 can be prepared by performing a substitution reaction in the case where a binding between Ring L and Ring Ar 2 in the Z 1 -L-Ar 2 , Z 2 -L-Ar 2 and Z 3 -L-Ar 2 is a N—C bond.
  • the reaction can be achieved, for example, by reacting Ring Ar 2 containing a halogen atom as substituent with Ring L containing a NH group in the ring in appropriate solvents or under solvent-free condition in the co-presence of alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example or potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali metal halides (for example, lithium chloride, cesium fluoride) or alkali metal hydroxides (for example, sodium hydroxide) and the others.
  • alkali carbonates for example, sodium carbonate, potassium carbonate or cesium carbonate
  • alkali phosphates for example or potassium phosphate
  • organic bases for example, triethylamine or diisopropylethylamine
  • alkali metal halides for example, lithium chloride, cesium fluoride
  • alkali metal hydroxides
  • the reaction may be achieved by performing a cross-coupling reaction on Ring L and Z 4 —Ar 2 (wherein Z 4 is a substituent on carbon atom in Ar 1 ring and represents a boronic acid, a boronate ester or a halogen atom) in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium or palladium acetate), copper catalysts (for example, copper iodide), zinc reagents or iron chelating reagents and the others optionally with an addition of phosphorus catalysts (for example, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl) or diamine reagents (typically, 1,2-diaminocyclohexane).
  • palladium catalysts typically, tetrakis(triphenylphosphin)palladium or palla
  • such coupling reactions may be carried out in the co-presence of alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal phosphates (for example, potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali hydroxides (for example, sodium hydroxide), metal alkoxides (for example, potassium t-butoxide) or the others, in addition to the above-mentioned reagents.
  • the compounds can be prepared, for example, according to the method described in J. Am. Chem. Soc. 1998, 120, 827-828, J. Am. Chem. Soc. 2001, 123, 7727-7729 or J. Org. Chem. 2002, 67, 1699-1702 or equivalent methods thereto.
  • the compounds of Z 1 -L-Ar 2 , Z 2 -L-Ar 2 and Z 3 -L-Ar 2 can be prepared by performing a substitution reaction on a commercially available Ring Ar 2 containing a NH group in the ring and a commercially available Ring L containing a halogen atom as substituent according to a conventional method. This reaction can be achieved according to the similar method to those of Process A-6.
  • solvents to be used for each reaction in Process A should be selected depending on the kind of the starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which may be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound of formula (I) can be prepared according to the below-mentioned processes.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined as above, X 2 represents a halogen atom (for example, iodine atom or bromine atom), and Z 5 represents a halogen atom, an amino group or a halogen atom)
  • the compound (III) can be prepared by performing a coupling reaction on the compound (IIb) and Z 1 -L-Z 5 (wherein Z 1 is the same as defined above, and Z 5 represents a halogen atom or a halogen atom) according to a conventional method. This reaction can be achieved according to the similar methods to those of Process A-1 (see Reference Examples 189 to 191).
  • the compounds (III) can be prepared by converting an X 2 group in the compound (IIb) into coupling reactive groups (for example, boron compound group, zinc halide group or magnesium halide group) according to the similar methods to those of Process A-2 followed by performing a coupling reaction on the resultant compounds and Z 2 -L-Z 5 (wherein, Z 2 and Z 5 are the same as defined above).
  • coupling reactive groups for example, boron compound group, zinc halide group or magnesium halide group
  • compound (I) can be prepared by performing a coupling reaction on the compound (III) and Z 1 —Ar 2 (wherein Z 1 is the same as defined above) according to a conventional method. This reaction can be achieved according to the similar methods to those of Process A-1 (see Examples 59 to 61).
  • the compound (I) can be prepared by performing a halogenation of a L group in the compound (III), followed by performing a coupling reaction of the resultant compounds with Z 1 —Ar 2 .
  • this halogenation reaction can be achieved by reacting the compound (III) with halogenating agents (for example, N-iodosuccinimide, N-bromosuccinimide, iodine or bromine), and the coupling reaction can be achieved according to the similar method to those of Process A-1.
  • halogenating agents for example, N-iodosuccinimide, N-bromosuccinimide, iodine or bromine
  • the compound (I) can be prepared by converting the Z 5 group into coupling reactive groups (for example, boron compound group, zinc halide group or magnesium halide group) according to the similar method to those of Process A-2 followed by performing a coupling reaction on the resultant compounds and Ring Ar 2 wherein halogen atom is substituted.
  • coupling reactive groups for example, boron compound group, zinc halide group or magnesium halide group
  • the compound (I) can be also prepared by converting the Z 5 group into halogen atom (for example, bromine atom or iodine atom) via Sandmeyer reaction according to a conventional method followed by performing a coupling reaction on the resultant compounds and Z 1 —Ar 2 according to the similar method to those of Process A-1.
  • the Sandmeyer reaction can be achieved by reacting the compound (III) with nitrites (typically, sodium nitrite) and copper halides (typically, copper bromide or copper iodide) in appropriate solvents or under solvent-free condition.
  • the compound (I) when L group in the compound (III) contains a NH group in the ring, that is, when a NH group is contained as a L-constituting group, the compound (I) can be prepared by performing a substitution reaction or a coupling reaction on the compound (III) and Z 4 —Ar 2 (wherein Z 4 is the same as defined above) according to a conventional method. This reaction can be achieved according to the similar method to those of Process A-6.
  • a coupling reaction between Ar 2 and L (step 2) can be applied to a coupling reaction in the case of a halogen atom on various substituents for R 1 or a halogen atom on Ar 1 .
  • solvents to be used for each reaction in Process B should be selected depending on the kind of starting materials and the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound (I) can be prepared according to the below-mentioned processes.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined above, X 2 represents a halogen atom, R x represents —C( ⁇ O)H or —CH(ORj) 2 and R j represents an alkyl group having one to six carbon atoms)
  • the compound (IV) can be prepared by performing a coupling reaction on the compound (IIb) and acetylene reagents according to a conventional method.
  • this reaction can be achieved by performing a cross-coupling reaction on the compound (IIb) and various acetylene reagents in appropriate solvents or under solvent-free condition in the co-presence of palladium catalyst (typically, tetrakis(triphenylphosphin)palladium), copper catalyst (typically, copper iodide), alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example, potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali hydroxides (for example, sodium hydroxide), metal alkoxides (for example, potassium t-butoxide) and the others (see Reference Example
  • the compound (I) wherein L represents a pyrazole ring can be prepared by performing a cyclization reaction on the compound (IV) according to a conventional method.
  • this reaction can be achieved by reacting the compound (IV) with Ar 2 —NH—NH 2 in appropriate solvents or under solvent-free condition.
  • the above-mentioned hydrazine compounds may be hydrochloride salts thereof, and the reaction may be optionally carried out in the presence of acids (for example, hydrochloric acid) (see Examples 1-29).
  • this reaction can be achieved by isolating hydrazine compound (as shown in the hydrazine compound of the below-mentioned structure (IV)-1 that produced as a reaction intermediate) followed by performing a cyclization reaction on the resultant compounds.
  • this cyclization reaction can be achieved in the presence of acids (for example, hydrochloric acid or sulfuric acid) or Lewis acids (for example, gold chloride) (see Example 30).
  • the compound (I) wherein L represents a pyrazole ring can be prepared by performing a cyclization reaction on the compound (IV) and hydrazines according to a conventional method followed by performing a coupling reaction on the resultant compounds and Z 4 —Ar 2 (wherein Z 4 is the same as defined above) according to the similar method to those of Process [A-6].
  • the hydrazines to be used in this reaction may be hydrates or hydrochloride salts thereof and the reaction may be optionally carried out in the presence of acids (for example, hydrochloric acid) or transition metal catalysts (for example, gold(III) chloride).
  • the compound of Ar 2 —NH—NH 2 can be prepared by converting the amino group into the hydrazine group according to a conventional method.
  • this reaction can be achieved by reacting the compounds with sodium nitrite or nitrite esters in the presence of acids (for example, hydrochloric acid) in appropriate solvents or under solvent-free condition followed by reacting the resultant compounds with reducing agents (for example, tin(II chloride) (see Reference Example 198).
  • solvents to be used for each step in Process C should be selected depending on the kind of starting materials and the kind of reagents used and includes, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1a represents an C 1-10 alkyl group substituted with C( ⁇ O)OR b or S( ⁇ O) m OR b , an C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1b represents a C 1-10 alkyl group substituted with —C( ⁇ O)OH or —S( ⁇ O) m OH
  • R 1c represents a C 1-10 alkyl group substituted with C( ⁇ O)NR c R d , S( ⁇ O)
  • the compound (Ib) can be prepared by performing a hydrolysis reaction on the compound (Ia) according to a conventional method.
  • this reaction can be achieved by performing a hydrolysis reaction in appropriate solvents or under solvent-free condition, under alkaline condition (for example, sodium hydroxide) or acidic condition (for example, hydrochloric acid) (see Examples 73 and 74).
  • the compound (Ib) can be prepared by performing a reduction reaction on the compound (Ia) according to a conventional method.
  • this reaction can be achieved by performing the reaction with catalytic reduction reagents (for example, palladium on carbon or palladium hydroxide) in charged states of hydrogen gas or in the presence of ammonium formate in appropriate solvents or under solvent-free condition, by performing the reaction in the presence of acids (for example, trifluoroacetic acid), or by performing the reaction in the presence of oxidizing agent (for example, 2,3-dichloro-5,6-dicyano-para-benzoquinone) (see Example 72).
  • catalytic reduction reagents for example, palladium on carbon or palladium hydroxide
  • acids for example, trifluoroacetic acid
  • oxidizing agent for example, 2,3-dichloro-5,6-dicyano-para-benzoquinone
  • the compound (Ic) can be prepared by performing an amidation reaction or an esterification reaction on the compound (Ib) according to a conventional method.
  • this reaction can be achieved by converting the compound (Ib) into reactive derivatives thereof (for example, active esters, anhydrides or acid halides) in appropriate solvents or under solvent-free condition followed by reacting the resultant compounds with various amines or various alcohols.
  • reactive derivatives thereof for example, active esters, anhydrides or acid halides
  • active ester examples include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester, 2-pyridylthiol ester, N-methylimidazole ester and the others.
  • the anhydrides may be used as symmetrical anhydrides or mixed anhydrides.
  • mixed anhydrides include mixed anhydrides of ethyl chlorocarbonate and isovaleric acid, and the others.
  • the compound (Ic) can be prepared by reacting the compound (Ib) with various amines and various alcohols in the presence of a condensing agent according to a conventional method.
  • a condensing agent include N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.monohydrochloride, N,N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate and the others.
  • These condensing agents may be used alone or in combination with peptide synthesis reagents (for example, N-hydroxysuccinimide or N-hydroxybenzotriazole) (see Examples 75-82).
  • ester group or the amidation reaction or esterification reaction shown in the above-mentioned processes may be applied to the case where the ester group on Ar 1 , L, Ar 2 and the others is converted into a carboxyl group, an amide group or an ester group (see Examples 103-106, Examples 142-145).
  • solvents to be used for each step in Process D should be selected depending on the kind of starting materials and the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1d represents a C 1-10 alkyl group substituted with NR a C( ⁇ O)OR b , a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1e represents a C 1-10 alkyl group substituted with NHR a , a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1f represents a C 1-10 alkyl group substituted with NR a C( ⁇ O)R b , NR a C( ⁇ O)NR c R d or NR a S( ⁇ O)
  • the compound (Ie) can be prepared by performing a deprotection of a carbamate group in the compound (Id) via a hydrolysis reaction or a reduction reaction.
  • this reaction can be achieved according to the similar method to those of [Step 1] in Process D (see Example 85).
  • the compound (If) can be prepared by performing an amidation reaction on the compound (Ie) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ie) with active ester, anhydrides or acid halides each being derivatized from carboxylic acid derivatives and sulfonic acid derivatives in appropriate solvents or under solvent-free condition.
  • active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester, 2-pyridylthiol ester, N-methylimidazole ester and the others.
  • the anhydrides may be used as symmetrical anhydrides or mixed anhydrides.
  • Specific examples of mixed anhydrides include a mixed anhydride of ethyl chlorocarbonate and isovaleric acid, and the others (see Example 86, Example 113).
  • the compound (If) can be prepared by reacting the compound (Ie) with various carboxylic acids and various sulfonic acids in the presence of a condensing agent according to a conventional method.
  • a condensing agent include N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride, N,N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate, and the others.
  • These condensing agents may be used alone or in combination with peptide synthesis reagents (for example, N-hydroxysuccinimide or N-hydroxybenzotriazole).
  • the compound (If) can be prepared by performing an urea formation on the compound (Ie) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ie) with various substituted isocyanate compounds and the others in appropriate solvents or under solvent-free condition. Also, the compound (If) can be prepared by converting the compound (Ie) into reactive derivatives thereof (for example, active carbamates) followed by reacting the resultant compounds with various amines according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ie) with phenyl chloroformate, carbodiimidazole or the others followed by reacting the resultant compounds with various amines in appropriate solvents or under solvent-free condition.
  • reactive derivatives thereof for example, active carbamates
  • Such urea formation reactions may be optionally carried out in metal hydride reagents (for example, sodium hydride or potassium hydride), inorganic bases (for example, potassium carbonate or sodium hydrogen carbonate) or organic bases (for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine).
  • metal hydride reagents for example, sodium hydride or potassium hydride
  • inorganic bases for example, potassium carbonate or sodium hydrogen carbonate
  • organic bases for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine.
  • the deprotection reaction of carbamate, an amidation reaction or an urea formation reaction as shown in the above-mentioned processes can be applied to the case of a deprotection reaction of a carbamate group, an amidation reaction or an urea formation reaction on Ar 1 , L, Ar 2 or R 1 other than the above-mentioned ones (see Example 112).
  • solvents to be used for Process E should be selected depending on the kind of starting materials or the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, or alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • solvents to be used for Process E should be selected depending on the kind of starting materials or the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 represents a C 1-10 alkyl group substituted with hydroxy, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ih)] can be prepared according to the below-mentioned processes.
  • R 1g represents a C 1-10 alkyl group substituted with CO 2 R b , C 2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1h represents a C 1-10 alkyl group substituted with hydroxy, a C 2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R b is the same as defined above
  • the compound (Ih) can be prepared by performing a reduction reaction on the compound (Ig) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ig) with reducing agents (for example, borane tetrahydrofuran complex or lithium aluminium hydride) in appropriate solvents, or alternatively when R b represents a hydrogen atom, can be achieved by reacting the compound (Ig) with anhydrides or acid halides so as to be derivatized to a mixed anhydrides, followed by treating the resultant mixed anhydrides with reducing agents (for example, sodium borohydride) (see Examples 83, 84 and 122).
  • reducing agents for example, sodium borohydride
  • the reduction reaction on ester group or carboxyl group as shown in the above-mentioned processes may be applied to the case of a reduction on the ester group or the carboxyl group on Ar 1 , L or Ar 2 (see Example 138).
  • solvents to be used in Process F should be selected depending on the kind of starting materials or the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 represents a C 1-10 alkyl group substituted with hydroxy, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ih)] can be prepared according to the below-mentioned processes.
  • R 1i represents a C 1-10 alkyl group substituted with OCOR a , a C 2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1h represents a C 1-10 alkyl group substituted with hydroxy, a C 2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R a is the same as defined above
  • the compound (Ih) can be prepared by performing a reduction reaction on the compound (Ii) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ii) with reducing agents (for example, diisobutylaluminium hydride or lithium aluminium hydride) in appropriate solvents.
  • reducing agents for example, diisobutylaluminium hydride or lithium aluminium hydride
  • the compound (Ih) can be prepared by performing a hydrolysis reaction on the compound (Ii) according to a conventional method.
  • this reaction can be achieved by performing a hydrolysis reaction on the compound (Ii) under basic condition with bases (for example, potassium carbonate or sodium hydroxide) or under acidic condition with acids (for example, hydrochloric acid) (see Examples 109-110).
  • bases for example, potassium carbonate or sodium hydroxide
  • acids for example, hydrochloric acid
  • solvents to be used in Process G should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound (Ik) can be prepared by performing a reduction reaction on the compound (Ij) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ij) with catalytic reduction reagents (for example, palladium on carbon or palladium hydroxide) in charged states of hydrogen gas or in the presence of ammonium formate, by performing a reaction in the presence of acids (for example, trifluoroacetic acid), or by performing a reaction in the presence of oxidizing agents (for example, 2,3-dichloro-5,6-dicyanopara-benzoquinone).
  • catalytic reduction reagents for example, palladium on carbon or palladium hydroxide
  • acids for example, trifluoroacetic acid
  • oxidizing agents for example, 2,3-dichloro-5,6-dicyanopara-benzoquinone
  • the compound (I) can be prepared by performing an alkylation reaction on the compound (Ik) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ik) with various alkylhalides reagents in the presence of hydrogenated metal reagents (for example, sodium hydride), alkali metal carbonates reagents (for example, potassium carbonate), alkali metal phosphates reagents (for example, potassium phosphate), organic bases reagents (for example, triethylamine), alkali metal halides reagents (for example, lithium chloride), alkali metal hydroxides (for example, sodium hydroxide), metal alkoxides (for example, potassium t-butoxide) or the others in appropriate solvents or under solvent-free condition.
  • hydrogenated metal reagents for example, sodium hydride
  • alkali metal carbonates reagents for example, potassium carbonate
  • alkali metal phosphates reagents for example, potassium phosphate
  • the compound (I) can be prepared by performing Mitsunobu reaction on the compound (Ik) and the corresponding alcohols according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ik) with the corresponding alcohols in the presence of a condensing agent (for example, a combination of triphenyl phosphine and diethyl azodicarboxylate) in appropriate solvents or under solvent-free condition.
  • a condensing agent for example, a combination of triphenyl phosphine and diethyl azodicarboxylate
  • solvents to be used in Process H should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined above, B a represents —NR a —, B b represents —NR a C( ⁇ O)—, and R a and R b are the same as defined above)
  • the compound (Im) can be prepared by performing an amidation reaction on the compound (Ii) according to the similar method to those of [Step 2] in Process E.
  • solvents to be used in Process I should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined above, B c represents —O— or —NR c —, and R d is the same as defined above)
  • the compound (Io) can be prepared by using the compound (In) according to the similar method to those of [Step 2] in Process H, or can be prepared by performing an alkylation reaction via a reductive amination on the compound (In) (see Example 141).
  • solvents to be used in Process J should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined above, B d represents a hydrogen atom, B e represents a halogen atom, B f represents —C( ⁇ O)—, B g represents —C( ⁇ O)NR c —, and R a and R d are the same as defined above)
  • the compound (Ig) can be prepared by performing a halogenation reaction on the compound (Ip) according to the similar method to those of [Step 2] in the Process B (see Examples 93 to 101).
  • the compound (Iq) wherein Be represents a fluorine atom can be prepared by performing a fluorination reaction on the compound (Ip) according to a conventional method. For example, this reaction can be achieved by reacting the compound (1) with fluorination agents (for example, Selectfluor (trade mark)) in appropriate solvents or under solvent-free condition (see Example 358).
  • fluorination agents for example, Selectfluor (trade mark)
  • the compound (Ir) can be prepared by performing a carbon monoxide insertion reaction on the compound (Iq) in the presence of alcohols (see Example 134).
  • the compound (Is) can be prepared by performing a hydrolysis reaction or a reduction reaction on the compound (Ir) according to the similar method to those of [Step 1] of Process D.
  • the compound (Is) can be prepared by performing a carbon monoxide insertion reaction on the compound (Iq) in the presence of water according to the similar method to those of [Step 2] of Process K (see Examples 132 to 133).
  • the compound (It) can be prepared by performing an amidation reaction on the compound (Is) according to the similar method to those of [Step 2] in Process D (see Examples 142 to 145).
  • solvents to be used for each step in the Process K should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • solvents to be used for each step in the Process K should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide,
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 1200° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 , Ar 1 , L, Ar 2 and R 2 are the same as defined above, B e represents a halogen atom, B h represents an optionally substituted alkyl group, an optionally substituted alkene group or a cyano group)
  • the compound (Iu) can be prepared by performing a coupling reaction on the compound (Iq). This reaction can be achieved according to the similar method to those of Process A-1. Also, a cyanation reaction can be achieved by using cyano coupling agents (for example, zinc cyanide or copper cyanide) (see Examples 126 to 131 and 363).
  • cyano coupling agents for example, zinc cyanide or copper cyanide
  • solvents to be used for each step in Process L should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1 represents a C 1-10 alkyl group substituted with alkoxy, alkylthio, alkylamino or dialkylamino, an C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Iw)] can be prepared according to the below-mentioned processes.
  • R 19 represents a C 1-10 alkyl group substituted with hydroxy, thio, amino, monoalkylamino, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1k represents a C 1-10 alkyl group substituted with alkoxy, alkylthio, alkylamino or dialkylamino, a C 2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • the compound (Iw) can be prepared by performing an alkylation reaction on the compound (Iv) according to the similar method to those of [Step 2] in Process H.
  • the method for an alkylation reaction shown in the above-mentioned processes can be also applied to the case where OH, SH, NH 2 or NHR a on Ar 1 , L or Ar 2 is alkylated.
  • solvents to be used in the Process M should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 11 represents a C 1-10 alkyl group substituted with acetal (CH(OR j ) 2 ), a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1m represents a C 1-10 alkyl group substituted with aldehyde, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1n represents a C 1-10 alkyl group substituted with monoalkylamino or dialkylamino, a C 2-6 alkene group or a three to six-membered saturated- or four to six
  • the compound (Iy) can be prepared by performing a deprotection reaction on acetal group in the compound (Ix) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ix) with acids (for example, p-toluenesulfonic acid, trifluoroacetic acid or hydrochloric acid) in appropriate solvents or under solvent-free condition (see Example 68).
  • acids for example, p-toluenesulfonic acid, trifluoroacetic acid or hydrochloric acid
  • the compound (Iz) can be prepared by performing a reductive amination reaction on the compound (Iy) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Iy) with monoalkylamine or dialkylamine in the co-presence of hydride reagents (for example, sodium borohydride, triacetoxysodium borohydride or sodium cyanoborohydride) and acids (for example, acetic acid or hydrochloric acid) in appropriate solvents or under solvent-free condition (see Examples 69 to 70).
  • hydride reagents for example, sodium borohydride, triacetoxysodium borohydride or sodium cyanoborohydride
  • acids for example, acetic acid or hydrochloric acid
  • the deprotection of acetal group as shown in the Step 1 of the above-mentioned processes may be applied to the case of a conversion reaction of acetal group on Ar 1 , L and Ar 2 into aldehyde group.
  • solvents to be used in Process N should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • R 1o represents a C 1-10 alkyl group substituted with hydroxy, aldehyde, thiol, alkylthio or sulfoxide, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1p represents a C 1-10 alkyl group substituted with aldehyde, oxo, carboxyl, sulfoxide or sulfonyl, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • R 1o in the compound (Ia′) represents a C 1-10 alkyl group substituted with hydroxy or aldehyde, a C 2-6 alkene group or a three- to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • the compound (Ia′) is oxidized according to a conventional method to produce the compound (Ib′) wherein R 1p represents a C 1-10 alkyl group substituted with oxo or carboxyl, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S.
  • this reaction can be achieved by reacting the compound (Ia′) with oxidizing agents (for example, Dess-Martin reagent, potassium dichromate
  • R 1o in the compound (Ia′) represents a C 1-10 alkyl group substituted with thiol or sulfoxide, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S
  • the compound (Ia′) can be oxidized according to a conventional method to produce the compound of the formula (Ib′) wherein R 1p represents a C 1-10 alkyl group substituted with sulfoxide or sulfonyl, a C 2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S.
  • this reaction can be achieved by reacting the compound (Ia′) with peroxidizing reagents (
  • the oxidation reaction as shown in the above-mentioned processes may be applied to the case of an oxidation reaction of methyl alcohol, methylthiol, aldehyde or sulfoxide as a substituent of Ar 1 , L and Ar 2 so as to convert it into aldehyde, carboxylic acid, sulfoxide or sulfonyl respectively.
  • solvents to be used for each reaction in Process O should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound (I) can be prepared according to the below-mentioned processes.
  • Ar 1 , L, Ar 2 , R 1 and R 2 are the same as defined above, and X 2 represents a halogen atom (for example, iodine atom or bromine atom).
  • the compound (Id′) can be prepared by performing a halogenation reaction on the compound (Ic′) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Ic′) with halogenating agents (for example, N-iodosuccinimide, N-bromosuccinimide, a combination of potassium iodide and cerium ammonium nitrate, iodine or bromine) in appropriate solvents or under solvent-free condition.
  • halogenating agents for example, N-iodosuccinimide, N-bromosuccinimide, a combination of potassium iodide and cerium ammonium nitrate, iodine or bromine
  • the compound (I) can be prepared by performing a coupling reaction on the compound (Id′) and Z 1 —R 2 (wherein Z 1 is the same as defined above) according to a conventional method. This reaction can be achieved according to the similar method to those of Process A-1.
  • the compound (I) can be prepared by performing an amination reaction on the compound (Id′) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Id′) with aminating agents (for example, ammonia, ammonium salt, alkylamine reagents or dialkylamine reagents) in appropriate solvents or under solvent-free condition.
  • aminating agents for example, ammonia, ammonium salt, alkylamine reagents or dialkylamine reagents
  • this reaction can be achieved by performing an amination reaction on the compound (Id′) and various amine reagents in the presence of palladium catalysts (for example, tetrakis(triphenylphosphin)palladium), copper reagents (for example, copper iodide), zinc reagents or iron chelating reagents, optionally with an addition of phosphorus catalyst (typically, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl).
  • palladium catalysts for example, tetrakis(triphenylphosphin)palladium
  • copper reagents for example, copper iodide
  • zinc reagents or iron chelating reagents optionally with an addition of phosphorus catalyst (typically, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t
  • the compound (I) can be prepared by performing a cyanation reaction on the compound (Id) according to a conventional method.
  • this reaction can be achieved by reacting the compound (Id′) with cyanating agents (for example, potassium cyanide, sodium cyanide or copper cyanide).
  • this reaction can be also achieved in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium), copper catalysts (typically, copper iodide), zinc reagents or iron chelating reagents, optionally with an addition of phosphorus catalyst (for example, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl).
  • palladium catalysts typically, tetrakis(triphenylphosphin)palladium
  • copper catalysts typically, copper iodide
  • zinc reagents or iron chelating reagents optionally with an addition of phosphorus catalyst (for example, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl).
  • phosphorus catalyst for example, 2,2′-bis(
  • solvents to be used in Process P should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
  • the starting materials (IIa) and (IIb) to be used in the above-mentioned Processes A to C are known compounds or are prepared, for example, according to the method shown in the below-mentioned reaction scheme.
  • the compound (IIa) represents the below-mentioned compound (VII) wherein X 3 represents a halogen atom or the below-mentioned compound (VIII) wherein X 3 represents an amino group
  • the compound (IIb) represents the below-mentioned compound (VII) wherein X 3 represents a halogen atom.
  • the compound (V) is a well-known compound or can be prepared according to equivalent processes to those for known compounds.
  • said compound can be prepared according to the method described in Journal of Medicinal Chemistry, 2004, 47(7), 1617-1630 and the others, or equivalent methods thereto.
  • the compound (VI) wherein R 2 represents a methyl group is a known compound or can be prepared by using the compound (V) according to equivalents processes to known processes.
  • said compound can be prepared according to the methods described in Heterocycles, 1993, 36(2), 307-314, J. Med. Chem. 2008, 51, 7478 and the others, or equivalent methods thereto.
  • the compound (VI) wherein R 2 represents an amino group is a known compound or can be prepared by using the compound (V) according to equivalent processes to known processes.
  • said compound can be prepared according to the method described in Chemical & Pharmaceutical Bulletin 1989, 37(8), 2008-2011 and the others or equivalent methods thereto.
  • the compound (VI) wherein R 2 represents a hydrogen atom is a known compound or can be prepared by using the compound (V) according to equivalent processes to known processes.
  • said compound can be prepared according to the methods described in Synthesis 1986, (12), 1041-1044 or equivalent processes thereto.
  • R 2 represents —N ⁇ CHN(CH 3 ) 2
  • R 2 represents —N ⁇ CHN(CH 3 ) 2
  • the compound (VI) and the compound (VII) wherein in both formulae, R 2 represents —N ⁇ CHN(CH 3 ) 2 can be performed a deprotection reaction under acidic condition (for example, hydrochloric acid or trifluoroacetic acid) or under alkali condition (for example, aqueous sodium hydroxide solution) so as to convert into the compound (VI) and the compound (VII) wherein in both formulae, R 2 represents NH 2 (see Reference Example 52, and Examples 57 and 58).
  • acidic condition for example, hydrochloric acid or trifluoroacetic acid
  • alkali condition for example, aqueous sodium hydroxide solution
  • the compound (VII) can be prepared by performing a halogenation reaction or a nitration reaction on the compound (VI) according to a conventional method.
  • the halogenation reaction can be achieved by reacting the compound (VI) with halogenating agents (for example, N-iodosuccinimide, N-bromosuccinimide, a combination of potassium iodide and ammonium cerium nitrate, iodine and bromine) in appropriate solvents or under solvent-free condition.
  • halogenating agents for example, N-iodosuccinimide, N-bromosuccinimide, a combination of potassium iodide and ammonium cerium nitrate, iodine and bromine
  • the nitration reaction can be achieved by reacting the compound (VI) with nitrating agents (for example, fuming nitric acid) in appropriate solvents or under solvent-free condition (see Reference Examples 60, 62-94 and 192).
  • the compound (VIII) can be prepared by performing a reduction reaction on the compound (VII) according to a conventional method.
  • this reaction can be achieved by reacting the compound (VII) with metal reagents (for example, palladium on carbon, platinum oxide, Raney nickel or reduced iron) in charged states of hydrogen gas or in the co-presence of ammonium chloride in appropriate solvents or under solvent-free condition (see Reference Examples 193 and 197).
  • metal reagents for example, palladium on carbon, platinum oxide, Raney nickel or reduced iron
  • the compound (VIII) can be prepared by performing an amination reaction on the compound (VII) according to a conventional method.
  • this reaction can be achieved by reacting the compound (VII) with amine reagents (for example, ammonia or ammonium salt) in appropriate solvents or under solvent-free condition.
  • solvents to be used for each reaction in Process P should be selected depending on the kind of starting materials and include, for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 200° C., preferably within a range of 0° C. to 150° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound (VI) wherein R 2 represents a hydrogen atom can be also prepared according to the below-mentioned reaction scheme.
  • the above-mentioned compound (VI) represents the compound (XIII) and the compound (XIV).
  • the compound (IX) is a known compound or can be prepared according to equivalent processes to a process for known compound.
  • said compound can be prepared, for example, according to the method described in Chemical & Pharmaceutical Bulletin, 1972, 20(7), 1380-1388 or equivalent methods thereto.
  • the compound (XI) is a known compound or can be prepared by using the compound (IX) and the compound (X) according to equivalent processes to a known process.
  • said compound can be prepared, for example, according to the method described in Chemical & Pharmaceutical Bulletin, 1972, 20(7), 1380-1388 or equivalent method thereto (see Reference Examples 111 and 115).
  • the compound (XII) is a known compound or can be prepared by performing a cyclization reaction on the compound (XI) according to equivalent processes to a known process.
  • said compound can be prepared, for example, according to the method described in Bioorganic & Medicinal Chemistry, 2006, 14(7), 3399-3404 and the others or equivalent methods thereto (see Reference Examples 112 and 116).
  • the compound (XIII) is a known compound or can be prepared by converting a cyano group in the compound (XII) into a hydrogen atom according to equivalent processes to known process.
  • said compound can be prepared, for example, according to a method described in Chemical & Pharmaceutical Bulletin, 1972, 20(7), 1389-1396 or equivalent methods thereto (see Reference Examples 113 and 117).
  • the compound (XIV) can be prepared, for example, in the presence of bases, by performing a reaction of the compound (XIII) with electrophilic reagents (for example, halogenated alkyl or carbamates), or by performing Mitsunobu reaction on the compound (XIII) and alcohols.
  • bases include metal hydrides (for example, sodium hydride), alkali or alkaline-earth carbonates (for example, potassium carbonate) or tertiary amine (for example, triethylamine) (see Reference Examples 100 and 101).
  • solvents to be used for each reaction in Process R should be selected depending on the kind of starting materials and include, for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which may be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents and the others, and includes usually within a range of ⁇ 40° C. to 200° C., preferably within a range of 0° C. to 150° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound (XIII) can be prepared according to the below-mentioned reaction scheme.
  • the compound (XV) is a known compound or can be prepared by reacting the compound (X) with acrylic acid according to equivalent processes to the known process.
  • said compound can be prepared, for example, according to the method described in WO 2009/39127 A1 and the others or equivalent methods thereto (see Reference Example 95).
  • the compound (XVI) is a known compound or can be prepared by reacting the compound (XV) with urea according to equivalent processes to known process.
  • said compound can be prepared, for example, according to the method described in WO 2009/39127 A1 and the others or equivalent methods thereto (see Reference Example 96).
  • the compound (XIII) can be prepared by reacting the compound (XVI) with bromine followed by the resultant compound with Lewis acids (for example, lithium chloride) or bases according to a conventional process.
  • Lewis acids for example, lithium chloride
  • said compound can be prepared, for example, according to the method described in Journal of Organic Chemistry, 2002, 67(5), 1480-1489, Journal of the American Chemical Society, 1956, 78, 1612-1614 or the others or equivalent methods thereto (see Reference Example 98).
  • solvents to be used in Process S should be selected depending on the kind of starting materials and the others and include, for example, water, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof.
  • the reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of ⁇ 40° C. to 200° C., preferably within a range of 0° C. to 100° C., and the reaction may be optionally carried out under pressurized condition.
  • the compound (XIII) can be also prepared according to the below-mentioned reaction scheme.

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Abstract

The present invention provides: an uracil derivative represented by general formula (I) or a physiologically acceptable salt thereof (in the formula, R1 represents a hydrogen atom, a C1-10 alkyl group, a C2-6 alkene group or a 3- to 6-membered saturated or 4- to 6-membered unsaturated aliphatic ring group which may contain 1 to 2 hetero atoms independently selected from the group consisting of N, O and S; R2 represents a hydrogen atom, a halogen atom, a cyano group, —NRcRd, —N═CHN(CH3)2, or an C1-3 alkyl group; Ar1 and Ar2 independently represent a 5- to 6-membered aromatic ring group which may contain 1 to 3 hetero atoms independently selected from the group consisting of N, O and S; and L represents a 6-membered aromatic ring group which may contain 1 to 4 nitrogen atoms, a pyrazole group, a triazole group, or an imidazole group); and a therapeutic agent or prophylactic agent for various inflammatory diseases associated with elastase, comprises the compound or the like as an active ingredient.
Figure US20140179670A1-20140626-C00001

Description

    TECHNICAL FIELD
  • The present invention provides a novel uracil derivative useful as medicament showing an elastase inhibitory activity. More specifically, the present invention provides a novel uracil derivative useful as a prophylactic agent and/or a therapeutic agent for various diseases associated with elastase such as inflammatory disease.
    • BACKGROUND ART
  • Human neutrophil elastase (hereinafter, sometimes referred to as solely “elastase”) is one kind of serine protease having a molecular weight of about 30 KDa and is stored in azurophilic granules of neutrophil. In physiological states, elastase takes, inside of neutrophils, a role for rapid digestion or degradation of phagocytized bacteria or exogenous materials, and takes, outside of neutrophils, roles for degradation of elastin, collagen (type III, type IV), proteoglycan, fibronectin which constitute interstitium of biological connective tissues such as lung, cartilage, blood vessel wall and skin, and for maintenance of tissue homeostasis.
  • In vivo, endogenous elastase-inhibiting proteins are existed. Among them, best known one is α1-antitrypsin (α1-AT), and patients with genetic defect of α1-AT are known to present chronic obstructive pulmonary disease (COPD) like-symptoms (see Non-Patent Literature-1). Like this case, when an imbalance occurs between endogenous elastase-inhibiting proteins and elastase, or when excess elastase is released due to pathological states such as inflammatory disease, it has been thought that elastase destroys normal tissues actively to cause various pathological conditions.
  • The diseases in which elastase is suggested to associate with pathological conditions include, for example, chronic obstructive pulmonary disease (COPD), pulmonary cystic fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic interstitial pneumonia (IIP), chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplantation, premature rupture of membrane, bullosa, shock, sepsis, systemic lupus erythematodes (SLE), Crohn disease, disseminated intravascular coagulation (DIC), ischemia-reperfusion induced-tissue injury, corneal scar tissue formation, myelitis, lung squamous cell carcinoma, pulmonary adenocarcinoma, lung cancers such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colorectal cancer, skin cancer, pancreas cancer, glioma and the others. Thus, an agent showing inhibitory activity for elastase is useful for treatment or prophylaxis of diseases associated with elastase.
  • With such an expectation, various elastase inhibitors have been reported. For example, Patent Literature-1 discloses 2-pyridone derivatives as neutrophil elastase inhibitor. In claim 1 of the Claims of the Literature, the compounds represented by the following general formula (A-1) (corresponding to formula I of said publication document) are described.
  • Figure US20140179670A1-20140626-C00002
  • In the formula, variables are defined as follows:
  • [wherein,
  • X represents O . . . ;
  • Y1 represents N . . . ; and when R1 represents OH, Y1 may also, in the tautomeric form, represent NR6;
  • Y2 represents CR3;
  • R1 represents . . . , when Y1 represents N, R1 may also represent OH;
  • . . . ]
  • If the above-mentioned definitions of X, Y1, Y2 and R1 are assigned to said formula (A-1), the formula (A-1) can be replaced by the following formula (A-2). Here, though there may be the compounds containing uracil backbone, they are clearly different in structure from the present compounds below-mentioned.
  • Figure US20140179670A1-20140626-C00003
  • Also, as compound showing p38 MAP kinase inhibitory activity, in each claim 1 of the Claims of Patent Literature-2 and Patent Literature-3 the compounds represented by the following general formula (A-3) (corresponding to formula I of said publication documents) are described.
  • Figure US20140179670A1-20140626-C00004
  • [wherein,
  • ring A represents a 5-membered mono-ring hetero ring which contains 1 to 3 atom(s) selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as a hetero atom, and which may have a further substituent(s);
  • ring B represents an optionally substituted hetero ring containing at least one nitrogen atom;
  • ring D represents an optionally substituted cyclic group;
  • ring E represents an optionally substituted cyclic group; and
  • R1 represents a substituent which contains nitrogen atom(s) having basicity] (see Patent Literature-2); and
  • [wherein
  • ring A represents a 5-membered mono-ring hetero ring which contains 1 to 3 atom(s) selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and which may have a further substituent(s);
  • ring B represents a hetero ring which may be substituted and may contain 1 to 3 atom(s) selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom in addition to the described nitrogen atom;
  • ring D represents a ring group which may be substituted;
  • ring E represents an optionally substituted cyclic group;
  • R1 represents a neutral group or an acidic group which contains an oxygen atom(s) and/or a sulfur atom(s)] (see Patent Literature-3).
  • However, in the compounds described specifically in Patent Literatures-2 and 3, a position of a substituent R1 that is substituted on five membered ring A is a 4th-position counting sequentially from the position binding to ring B, then ring D, while in the present compounds, ring A (corresponding to L of formula (I) described herein) is unsubstituted and a position of a substituent on ring A (corresponding to L of formula (I) described herein) is a 5th-position, which are different each other in structure.
    • RELATED ART DOCUMENTS Patent Documents
    • [Patent Literature-1]: WO 2004/043924 pamphlet
    • [Patent Literature-2]: WO 2006/051826 pamphlet
    • [Patent Literature-3]: WO 2007/040208 pamphlet
    Non-Patent Documents
    • [Non-patent Literature-1]: Eur. Respir. J. 2009, 33, 1345-1353
    DISCLOSURE OF INVENTION Problems to be Solved by Invention
  • An object of the present invention is to provide a therapeutic agent for various inflammatory diseases associated with elastase.
    • Means to Solve Problems
  • The present inventors have intensively studied and as a result, they have found out that the novel compounds represented by the following formula (I) show an elastase inhibitory activity, and have therefore completed the present invention. According to the present invention, uracil derivatives represented by the following formula (I) (hereinafter, sometimes referred to as “Present compound”) is provided.
  • A compound represented by formula (I) or physiologically acceptable salts thereof:
  • Figure US20140179670A1-20140626-C00005
  • [wherein
  • R1 represents a hydrogen atom, a C1-10 alkyl group, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group and said alkene group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 1:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O) Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (7) three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, cyano, —NRaC(═O)Rb, —NRaC(═O)NRcRd, —NRaS(═O)mRb, —C(═O)ORb, —C(═O)NRcRd or —NRcRd),
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —C(═O)Rb,
      • —S(═O)mNRcRd,
      • —S(═O)mRb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (9) —OC(═O)NRcRd group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group,
  • (12) thiol group,
  • (13) nitro group and
  • (14) —ORe group,
  • said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 2:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three- to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or a —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (8) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group,
  • (13) thiol group,
  • (14) oxo group,
  • (15) nitro group,
  • (16) —NRaC(═O)Rb group,
  • (17) —NRaC(═O)NRcRd group,
  • (18) —NRaS(═O)mRb group,
  • (19) —C(═O)ORb group and
  • (20) —C(═O)NRcRd group,
  • R2 represents a hydrogen atom, a halogen atom, a cyano group, a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra),
  • Ar1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O) Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • L represents a six membered aromatic ring group optionally containing one to four nitrogen atoms, a Pyr-1 group of the following formula, a Tri-1 group of the following formula or an Imi-1 group of the following formula:
  • Figure US20140179670A1-20140626-C00006
  • (in each formula,
  • the bond 1 represents a binding to uracil ring, the bond 2 represents a binding to Ar2, and the Z1, Z2 and Z3 represents independently of each other a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORa group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rb group, a hydrogen atom, a C1-6 alkyl group or a C2-6 alkene group, and said alkyl group and said alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa),
  • wherein, when L represents a six membered aromatic ring group, the L may be optionally substituted at substitutable positions with halogen, —C(═O)NRcRd, —C(═O)ORa, hydroxy, —NRcRd, nitro, —NRaC(═O)Rb, C1-6 alkyl or C2-6 alkene, and said alkyl and said alkene may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa,
  • Ar2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or more substitutable positions with C1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O) Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • Ra represents a hydrogen atom or a C1-6 alkyl group optionally substituted with hydroxy or halogen,
  • Rb represents a hydrogen atom, a C1-6 alkyl group optionally substituted with hydroxy or halogen, a benzyl group optionally substituted with methoxy or nitro, or a C3-6 cycloalkyl group optionally substituted with hydroxy or halogen,
  • Rc and Rd represents independently of each other a hydrogen atom, or a C1-3 alkyl group optionally substituted with hydroxy or halogen, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl, hydroxy, halogen or oxo),
  • Re represents
  • a hydrogen atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group,
    a —C(═O)-A group,
    a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
    a C1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen),
    a —C(═O)NRcRd group or
    a —S(═O)mRb group,
  • Rf represents
  • a hydrogen atom,
    a hydroxy group,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    a C1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group),
    an -A group or
    a —NRaRi group,
  • Rg represents
  • a hydroxy group,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group or
    a —NRaRi group,
  • Rh represents a C1-6 alkyl group optionally substituted with hydroxy or halogen,
  • Ri represents
  • a hydrogen atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy, C3-6 cycloalkyl or —NRcRd),
    an -A group,
    a —C(═O)Rb group,
    a —C(═O)A group or
    a C1-6 alkyl carbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
  • A represents
  • a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group) or
    a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group),
  • m represents an integer of one (1) or two (2) and
  • n represents an integer of zero (0) to two (2)].
  • The compound according to [1] or physiologically acceptable salts thereof wherein
  • R1 represents a hydrogen atom, a C1-10 alkyl group, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group and said alkene group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 3:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkyl group optionally substituted with
      • hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)Rb,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (9) —OC(═O)NRcRd group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group and
  • (12) thiol group,
  • said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 4:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (8) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group,
  • (13) thiol group and
  • (14) oxo group,
  • R2 represents a hydrogen atom, a halogen atom, a cyano group, a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra),
  • Ar1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one or multiple substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • L represents a six-membered aromatic ring group optionally containing one to four nitrogen atoms, a Pyr-1 group of the following formula, a Tri-1 group of the following formula or an Imi-1 group of the following formula:
  • Figure US20140179670A1-20140626-C00007
  • (in each formula, the bond 1 represents a binding to uracil ring, the bond 2 represents a binding to Ar2, and the Z1, Z2 and Z3 represent independently of each other a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORa group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rb group, a hydrogen atom, a C1-6 alkyl group or a C2-6 alkene group, and said alkyl group and said alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa),
  • wherein, when L represents a six-membered aromatic ring group, the L may be optionally substituted at substitutable positions with halogen, —C(═O)NRcRd, —C(═O)ORa, hydroxy, —NRcRd, nitro, —NRaC(═O)Rb, C1-6 alkyl group or C2-6 alkene group, and said alkyl group and said alkene group may independently of each other be optionally substituted at substitutable positions with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa;
  • Ar2 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one or multiple substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • Ra represents a hydrogen atom or a C1-6 alkyl group optionally substituted with hydroxy or halogen,
  • Rb represents a hydrogen atom, a C1-6 alkyl group optionally substituted with hydroxy or halogen or a benzyl group optionally substituted with methoxy or nitro,
  • Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group optionally substituted with hydroxy or halogen, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl, hydroxy or halogen),
  • Re represents
  • a hydrogen atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group,
    a —C(═O)-A group,
    a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
    a C1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen),
    a —C(═O)NRcRd group or
    a —S(═O)mRb group,
  • Rf represents
  • a hydrogen atom,
    a hydroxy group,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    a C1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group),
    an -A group or
    a —NRaRi group,
  • Rg represents
  • a hydroxy group,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group or
    a —NRaRi group,
  • Rh represents a C1-6 alkyl group optionally substituted with hydroxy or halogen,
  • Ri represents
  • a hydrogen atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group,
    a —C(═O)A group,
    a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
  • A represents
  • a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group) or
    a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group),
  • m represents an integer of 1 or 2 and
  • n represents an integer of zero (0) to two (2).
  • [3]
  • The compound according to [1] or [2] or physiologically acceptable salts thereof wherein R1 represents a C1-10 alkyl group (said alkyl group may be optionally substituted with one or multiple substituents described in Substituent List 3), a C2-6 alkene group (said alkene group may be optionally substituted with one or multiple substituents described in Substituent List 3) or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted with one or multiple substituents described in Substituent List 4).
  • [4]
  • The compound according to any one of [1] to [3] or a physiologically acceptable salts thereof wherein R2 represents a hydrogen atom, a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra).
  • [5]
  • The compound according to any one of [1] to [4] or physiologically acceptable salts thereof, wherein Ar1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group.
  • [6]
  • The compound according to any one of [1] to [5] or a physiologically acceptable salts thereof, wherein
  • Ar1 represents an Ar1-1 group of the following formula:
  • Figure US20140179670A1-20140626-C00008
  • (in the formula,
  • K1, K2, K3 and K4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and
  • X represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group;
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K1 to K4 with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group.
  • [7]
  • The compound according to any one of [1] to [6] or physiologically acceptable salts thereof wherein
  • Ar2 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group.
  • [8]
  • The compound according to any one of [1] to [7] or physiologically acceptable salts thereof wherein
  • Ar2 represents an Ar2-1 group of the following formula:
  • Figure US20140179670A1-20140626-C00009
  • (in the formula,
  • L1, L2, L3 and L4 represents all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and
  • Y represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L1 to L4 with C1-6 alkyl group optionally substituted with hydroxy or halogen, or C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group).
  • [9]
  • The compound according to any one of [1] to [8] or physiologically acceptable salts thereof wherein the formula (I) represents the following formula (I′):
  • Figure US20140179670A1-20140626-C00010
  • (in the formula,
  • L represents a benzene ring or a pyridine ring, and the position on which said benzene ring and said pyridine ring are attached to the uracil ring is an or to position to the position on which said benzene ring and the pyridine ring are attached to the Ar2;
  • said benzene ring and the pyridine ring may independently of each other be optionally substituted with C1-6 alkyl group optionally substituted with one or multiple substituents selected from the group consisting of halogen, hydroxy, —NRcRd, —C(═O)NRcRd and —C(═O)ORa, halogen atom, —C(═O)NRcRd group, —C(═O)ORa group, —NRcRd group, nitro group or —NRaC(═O)Rb group).
  • [10]
  • The compound according to any one of [1] to [9] or physiologically acceptable salts thereof wherein L represents an unsubstituted benzene ring or an unsubstituted pyridine ring.
  • [11]
  • The compound according to any one of [1] to [8] or physiologically acceptable salts thereof wherein the L represents a group of Pyr-1, Tri-1 or Imi-1, and the Z1, Z2 and Z3 represent a hydrogen atom.
  • [12]
  • The compound according to any one of [1] to [8] or physiologically acceptable salts thereof wherein the L represents a group of Pyr-1, Tri-1 or Imi-1, and the Z1, Z2 and Z3 represent independently of each other a C1-6 alkyl group optionally substituted with —NRcRd or halogen, a halogen atom, a —NRcRd group or a nitro group.
  • [13]
  • The compound according to any one of [1] to [8] or physiologically acceptable salts thereof wherein the L represents a group of Pyr-1, Tri-1 or Imi-1, and the Z1, Z2 and Z3 represent independently of each other a C1-6 alkyl group optionally substituted with —C(═O)NRcRd, a —C(═O)NRcRd group or a —NRaC(═O)Rb group.
  • [14]
  • The compound according to any one of [1] to [8] or physiologically acceptable salts thereof wherein the L represents a group of Pyr-1, Tri-1 or Imi-1, and the Z1, Z2 and Z3 represent independently of each other a C1-6 alkyl group optionally substituted with hydroxy or —C(═O)ORa, a hydroxy group or a —C(═O)ORa group.
  • [15]
  • The compound according to any one of [1] to [14] or physiologically acceptable salts thereof wherein R1 represents a C1-10 alkyl group optionally substituted at substitutable positions with one or multiple substituents described in Substituent List 3, or a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S that may be optionally substituted at substitutable positions with one or multiple substituents described in Substituent List 4.
  • [16]
  • The compound according to any one of [1] to [15] or physiologically acceptable salts thereof wherein
  • R1 represents a C1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 5:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRe,
      • —C(═O)Rb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (9) —OC(═O)NRcRd group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group and
  • (12) thiol group.
  • [17]
  • The compound according to any one of [1] to [16] or physiologically acceptable salts thereof wherein
  • R1 represents a C1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
    • Substituent List 6:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with one or multiple substituents selected from the group consisting of hydroxy and halogen,
      • C1-3 alkoxy group optionally substituted with one or multiple substituents selected from the group consisting of hydroxy and halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —C(═O)Rb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group, and
  • (10) —C(═O)Rf group.
  • [18]
  • The compound according to any one of [1] to [15] or physiologically acceptable salts thereof wherein
  • R1 represents a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S that may be optionally substituted at substitutable positions with one or multiple substituents described in Substituent List 4.
  • [19]
  • The compound according to any one of [1] to [15] and [18] or physiologically acceptable salts thereof wherein
  • R1 represents a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 7:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group), or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (8) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group and
  • (14) oxo group.
  • [20]
  • The compound according to any one of [1] to [15], [18] and [19] or physiologically acceptable salts thereof wherein R1 represents a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S that may be optionally substituted with one or multiple substituents described in Substituent List 7, and said aliphatic ring group represents C3-6 saturated carbocycle, aziridine, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, morpholine or piperazine.
  • [21]
  • The compound according to any one of [1] to [20] or physiologically acceptable salts thereof, wherein
  • Ra represents a hydrogen atom or a C1-6 alkyl group optionally substituted with hydroxy or fluorine,
  • Rb represents a C1-6 alkyl group optionally substituted with hydroxy or fluorine,
  • Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group optionally substituted with hydroxy or fluorine, or alternatively combine each other together with N (nitrogen atom) to which they are attached and optionally together with further O (oxygen atom) to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine),
  • Re represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, fluorine, C1-3 alkoxy or —NRcRd), an -A group, a —C(═O)-A group, a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, fluorine, cyano, C1-3 alkoxy or —NRcRd), a —C(═O)NRcRd group or a —S(═O)mRb group,
  • Rf represents a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, fluorine or —NRcRd) or a —NRaRd group,
  • Rg represents a hydroxy group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, fluorine or —NRcRd) or a —NRaRi group,
  • Rh represents a C1-3 alkyl group optionally substituted with hydroxy or fluorine,
  • Ri represents a C1-6 alkyl group (said alkyl group may be optionally substituted with fluorine or —NRcRd), an -A group, a —C(═O)-A group or a C1-6 alkyl carbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with fluorine or —NRcRd),
  • A represents
  • an aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group) or
    an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group), and
  • m represents 1 or 2.
  • [22]
  • The compound according to any one of [1] to [8], [15] and [21] or physiologically acceptable salts thereof, wherein the formula (I) represents the following formula (I″):
  • Figure US20140179670A1-20140626-C00011
  • [wherein,
  • L represents a benzene ring (wherein, the position on which said benzene ring is attached to the uracil ring is an orto position to the position on which said benzene ring is attached to the Ar2, and said benzene ring may be optionally substituted at substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, —C(═O)NRcRd group or —C(═O)OH group), or a group of Pyr-1 or Tri-1 of the following formula:
  • Figure US20140179670A1-20140626-C00012
  • (in each formula,
  • the bond 1 represents a binding to uracil ring, the bond 2 represents a binding to Ar2, and the Z1 and Z2 represent independently of each other a C1-6 alkyl group optionally substituted with a halogen atom, a hydroxy group, a —NRcRd group, —C(═O)NRcRd or —C(═O)OH group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)OH group, a —NRcRd group or a hydrogen atom),
  • R1 represents
  • a C1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
  • (1) hydroxy group,
  • (2) halogen atom,
  • (4) C1-6 alkoxy group (said alkoxy group may be substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom or —C(═O)OH group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, —C(═O)ORb group, —C(═O)NRcRd group or oxo group),
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom or
      • —C(═O)ORb),
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, —C(═O)ORb group, —C(═O)NRcRd group, —C(═O)Rb group or oxo group) and
  • (8) —NRaRe group)
  • or
    a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with hydroxy or halogen),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with hydroxy or halogen),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group and
  • (14) oxo group,
  • R2 represents a halogen atom, a —NRcRd group, or a C1-3 alkyl group optionally substituted with —ORa or —OC(═O)Ra,
  • X represents a C1-3 alkyl group optionally substituted with one or multiple fluorine atoms or a nitro group,
  • Y represents a cyano group, a chlorine atom or a nitro group,
  • Ra represents a hydrogen atom, or a C1-3 alkyl group optionally substituted with hydroxy or fluorine,
  • Rb represents a C1-3 alkyl group optionally substituted with one to three fluorine atoms,
  • Rc and Rd represent independently of each other a C1-3 alkyl group optionally substituted with fluorine or a hydrogen atom, or alternatively combine each other together with N to which they are attached to represent pyrrolidine or piperidine,
  • Re represents a C1-6 alkyl group (said alkyl group may be optionally substituted with fluorine or —NRcRd), an -A group, a —C(═O)-A group, a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with fluorine or —NRcRd) or a —S(═O)2Rb group,
  • Rf represents a hydroxy group or a —NRaRi group,
  • Rg represents a C1-3 alkyl group,
  • Rh represents a C1-3 alkyl group optionally substituted with fluorine,
  • Ri represents a C1-3 alkyl group (said alkyl group may be optionally substituted with fluorine or —NRcRd) or an -A group,
  • A represents an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group) and
  • m represents 2].
  • [23]
  • The compound according to any one of [1] to [8], [15] and [21] to [22] or physiologically acceptable salts thereof wherein the Z1 and Z2 represent a hydrogen atom.
  • [24]
  • A compound represented by formula (I) or physiologically acceptable salts thereof:
  • Figure US20140179670A1-20140626-C00013
  • [wherein
  • R1 represents a hydrogen atom, a C1-10 alkyl group, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • said alkyl group and said alkene group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 1:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)ORb,
      • —C(═O) NRcRd,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (7) three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, cyano, —NRaC(═O)Rb, —NRaC(═O)NRcRd, —NRaS(═O)mRb, —C(═O)ORb, C(═O)NRcRd or —NRcRd),
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —C(═O)Rb,
      • —S(═O)mNRcRd,
      • —S(═O)mRb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (9) —OC(═O)NRcRd group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group,
  • (12) thiol group,
  • (13) nitro group and
  • (14) —ORe group,
  • said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 2:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three- to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRaRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or a —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (8) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group,
  • (13) thiol group,
  • (14) oxo group,
  • (15) nitro group,
  • (16) —NRaC(═O)Rb group,
  • (17) —NRaC(═O)NRcRd group,
  • (18) —NRaS(═O)mRb group,
  • (19) —C(═O)ORb group and
  • (20) —C(═O)NRcRd group,
  • R2 represents a hydrogen atom, a halogen atom, a cyano group, a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra),
  • Ar1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O) Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • L represents a six membered aromatic ring group optionally containing one to four nitrogen atoms, a Pyr-1 group of the following formula, a Tri-1 group of the following formula or an Imi-1 group of the following formula:
  • Figure US20140179670A1-20140626-C00014
  • (in each formula,
  • the bond 1 represents a binding to uracil ring, the bond 2 represents a binding to Ar2, and the Z1, Z2 and Z3 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —CHO group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rh group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mR2 group, a —S—Rg3 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, a C1-6 alkyl group or a C2-6 alkene group, and said alkyl group and an alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd, —NRaS(═O)mRh or —C(═O)ORa, and said saturated aliphatic ring group may be optionally substituted with hydroxy, halogen, C1-6 alkyl, C1-3 alkoxy, —C(═O)ORa, —C(═O)Ra or —NRaRb),
  • wherein, when L represents a six-membered aromatic ring group, the L may be optionally substituted at substitutable positions with halogen, —C(═O)NRcRd, —C(═O)ORa, hydroxy, —NRcRd, nitro, —NRaC(═O)Rb, C1-6 alkyl or C2-6 alkene, and said alkyl and said alkene may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa,
  • Ar2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or more substitutable positions with C1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • Ra represents a hydrogen atom or a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen),
  • Rb represents a hydrogen atom, a C1-6 alkyl group optionally substituted with hydroxy or halogen, a benzyl group optionally substituted with methoxy or nitro, or a C3-6 cycloalkyl group optionally substituted with hydroxy or halogen,
  • Rb2 represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb or halogen), a benzyl group (said benzyl group may be optionally substituted with methoxy or nitro) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen),
  • Rb3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen),
  • Rb4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen) or an 2-isopropyl-5-methylcyclohexyl,
  • Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group optionally substituted with C1-3 alkoxy, cyano, hydroxy or halogen, or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb, —NRaC(═O)ORh or —NRaC(═O)Rh), C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O) Rh group, —C(═O)ORa group, hydroxy group, halogen atom or oxo group),
  • Rc2 and Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or halogen atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group, C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, halogen atom or oxo group),
  • Re represents
  • a hydrogen atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group,
    a —C(═O)-A group,
    a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
    a C1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen),
    a —C(═O)NRcRd group or
    a —S(═O)mRb group,
  • Rf represents
  • a hydrogen atom,
    a hydroxy group,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    a C1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group),
    an -A group or
    a —NRaRi group,
  • Rg represents
  • a hydroxy group,
    a chlorine atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
    an -A group or
    a —NRaRi group,
  • Rg2 represents
  • a hydroxy group,
    a chlorine atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd) or
    an -A group,
  • Rg3 represents
  • a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or NRcRd) or
    an -A group,
  • Rb represents a C1-6 alkyl optionally substituted with hydroxy or halogen,
  • Ri represents
  • a hydrogen atom,
    a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy, C3-6 cycloalkyl or —NRcRd),
    an -A group,
    a —C(═O)Rh group,
    a —C(═O)A group or
    a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
  • A represents
  • a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group),
    a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group),
  • m represents an integer of 1 or 2 and
  • n represents an integer of 0 to 2].
  • [25]
  • The compound according to [24] or physiologically acceptable salts thereof, wherein
  • L represents
  • a six membered unsubstituted aromatic ring group optionally containing 1 to 2 nitrogen atoms, a Pyr-1 group of the following formula or a Tri-1 group of the following formula:
  • Figure US20140179670A1-20140626-C00015
  • (in each formula,
  • the bond 1 represents a binding to uracil ring, the bond 2 represents a binding to Ar2, and the Z1 and Z2 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —CHO group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rh group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a —S—Rg3 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted with hydroxy, halogen, C1-6 alkyl, C1-3 alkoxy, —C(═O)ORa, —C(═O)Ra or —NRaRb), a C1-6 alkyl group or a C2-6 alkene group (said alkyl group and said alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd, —NRaS(═O)mRh or —C(═O)ORa).
  • [26]
  • The compound according to [24] or [25] or physiologically acceptable salts thereof, wherein
  • Z1 and Z2 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —CHO group, a nitro group, a —NRaC(═O)Rb group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted with halogen, C1-6 alkyl, —C(═O)ORa or —C(═O)Ra) or a C1-6 alkyl group (said alkyl group may be optionally substituted with halogen, —C(═O)NRcRd, —NRaS(═O)mRh, —C(═O)NRcRd or —C(═O)ORa).
  • [27]
  • The compound according to any one of [24] to [26] or physiologically acceptable salts thereof wherein
  • Ar1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group), and
  • Ar2 represent a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are substituted independently of each other at one to three substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group).
  • [28]
  • The compound according to any one of [24] to [27] or physiologically acceptable salts thereof wherein
  • Ar1 represents the following formula of Ar1-1:
  • Figure US20140179670A1-20140626-C00016
  • (in the formula, K1, K2, K3 and K4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and X represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O) Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K1 to K4 with further C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group),
  • Ar2 represents the following formula Ar2-1:
  • Figure US20140179670A1-20140626-C00017
  • (in the formula, L1, L2, L3 and L4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and Y represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L1 to L4 with further C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group).
  • [29]
  • The compound according to any one of [24] to [28] or physiologically acceptable salts thereof wherein R2 represents a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra).
  • [30]
  • The compound according to any one of [24] to [29] or physiologically acceptable salts thereof, wherein
  • Ra represents a hydrogen atom or a C1-6 alkyl group optionally substituted with hydroxy or halogen,
  • Rb represents a C1-6 alkyl group optionally substituted with hydroxy or halogen,
  • Rb2 represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb or fluorine) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine),
  • Rb3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine or chlorine), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine),
  • Rb4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine or chlorine), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine) or an 2-isopropyl-5-methylcyclohexyl,
  • Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with C1-3 alkoxy, cyano, hydroxy or fluorine), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb, —NRaC(═O)ORh or —NRaC(═O)Rh), C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORa group, —NRaC(═O)Ra group, —C(═O)ORa group, hydroxy group, fluorine atom or oxo group),
  • Rc2 an Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl, C1-3 alkoxy, —NRaRb, —NRaC(═O)ORh, —NRaC(═O) Rh, —C(═O)ORa, hydroxy, fluorine or oxo),
  • Re represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), an -A group, a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy or fluorine) or a —S(═O)2Rb group,
  • Rf represents a hydroxy group, an -A group or an —NRaRi group,
  • Rg represents a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, fluorine or —NRcRd), a chlorine atom, an -A group or a —NRaRi group,
  • Rg2 represents a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), a chlorine atom or an -A group,
  • Rg3 represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, fluorine or —NRcRd),
  • Rh represents a C1-3 alkyl group optionally substituted with hydroxy or fluorine,
  • Ri represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, C1-3 alkoxy or fluorine) or an -A group,
  • A represents
  • an aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine) or
    an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl, C1-3 alkoxy, hydroxy, fluorine, —NRcRd or oxo), and
  • m represents an integer of 1 or 2.
  • [31]
  • The compound according to any one of [24] to [30] or physiologically acceptable salts thereof wherein
  • R1 represents a C1-10 alkyl group (said alkyl group may be substituted at substitutable positions with one to three substituents selected from the group consisting of
    • Substituent List 8:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —C(═O)Rb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group, and
  • (12) thiol group,
  • or
    a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 9:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or a —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group, and
  • (14) oxo group.
  • [32]
  • The compound according to any one of [24] to [31] or physiologically acceptable salts thereof wherein
  • R1 represents
  • a C1-10 alkyl group (said alkyl group may be substituted at substitutable positions with one to three substituents selected from the group consisting of
    • Substituent List 10:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy, halogen, —C(═O)ORb, —C(═O)NRcRd, —C(═O)Rb or oxo group),
  • (8) —NRaRe group, and
  • (11) —S(═O)2Rg group)
  • or
    a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 11:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with hydroxy or halogen),
  • (9) —NRaRe group,
  • (11) —C(═O)Rf group and
  • (14) oxo group.
  • [33]
  • The compound according to any one of [24] to [32] or physiologically acceptable salts thereof wherein L represents a Pyr-1 group.
  • [34]
  • The compound according to any one of [24] to [33] or physiologically acceptable salts thereof wherein
  • the formula (I) represents the following formula (I′″):
  • Figure US20140179670A1-20140626-C00018
  • (wherein, Z1 represents a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a hydrogen atom, a —S(═O)2NRc2Rd2 group, a —S(═O)2NRaC(═O)Rb3 group, a —S(═O)2NRaC(═O)ORb4 group, a —S(═O)2NRaC(═O)NRaRb3 group or a S(═O)2Rg group,
  • X represents a C1-3 alkyl group optionally substituted one or multiple fluorine atoms or a nitro group, and
  • Y represents a cyano group, a chlorine atom or a nitro group).
  • [35]
  • The compound according to [34] or physiologically acceptable salts thereof wherein
  • Z1 represents a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —S(═O)2NRc2Rd2 group, a —S(═O)2NRa2C(═O)Rb3 group, a —S(═O)2NRaC(═O)ORb4 group, a —S(═O)2NRaC(═O)NRaRb3 group, a S(═O)2Rg group, an iodine atom, a bromine atom or a chlorine atom, and
  • R2 represents a C1-3 alkyl group optionally substituted with hydroxy.
  • [36]
  • The compound according to [1] or [24] selected from the following Group or physiologically acceptable salts thereof,
    • Group:
    • 4-[5-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,
    • 4-[5-[6-Methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,
    • 4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • 4-[5-[1-(3-Chlorophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,
    • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • 4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • 4-(5-(6-Ethyl-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • (R)-4-(5-(3-(1-Hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl) berxzonitrile,
    • 4-(4-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile,
    • (S)-4-(5-(2,4-Dioxo-3-(5-oxopyrrolidin-3-yl) 1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • 1-(4-Cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide,
    • 4-(Dimethylamino)butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate,
    • (±)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,
    • (+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,
    • (−)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3 trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,
    • (±)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3 trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
    • (−)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3 trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
    • (+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3 trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
    • (+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3 trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide.0.5 IPA solvates,
    • (±)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
    • (+)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
    • N-(1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonyl)pivalamine,
    • Butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonylcarbamate,
    • N-(1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonyl)benzamide,
    • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(ethylcarbonyl)-1H-pyrazole-4-sulfonamide,
    • (±)-4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,
    • (+)-4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,
    • (±)-4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,
    • 4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzonitrile,
    • (R)-4-(5-(6-Methyl-2,4-dioxo-3-(pyrrolidin-3-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile,
    • 4-(4-Chloro-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carbonitrile,
    • (R)-4-(5-(6-Methyl-3-(methanesulfonyl)propan-2-yl)-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
    • (R)-2-(5-(1-(4-Cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonamide and
    • 5-(4-Cyanophenyl)-4-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazole-3-carboxamide.
      [37]
  • A pharmaceutical composition comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof as active ingredient and a pharmaceutical carrier.
  • [38]
  • An esterase inhibitor comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof as active ingredient.
  • [39]
  • An agent for treatment or prophylaxis of inflammatory diseases comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof.
  • [40]
  • An agent for treatment or prophylaxis of diseases required for elastase inhibitory activity comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof.
  • Also, the present application provides the following aspects:
  • [41]
  • Use of the compound according to any one of [1] to [36] or physiologically acceptable salts thereof in a preparation of medicine for treatment or prophylaxis of inflammatory diseases.
  • [42]
  • A pharmaceutical composition for use in treatment or prophylaxis of inflammatory diseases comprising the compound according to any one of [1] to [36] or physiologically acceptable salts thereof as active ingredient.
  • [43]
  • A method for treatment or prophylaxis of inflammatory diseases which comprises administering a therapeutically effective amount of the compound according to any one of [1] to [36] or physiologically acceptable salts thereof into a patient in need thereof.
    • Effect of Invention
  • The present invention can provide compounds showing elastase inhibitory activity, and thereby can provide a therapeutic agent or a prophylactic agent for diseases associated with elastase such as inflammatory diseases. The diseases in which elastase is suggested to associate with pathological conditions include, for example, chronic obstructive pulmonary disease (COPD), pulmonary cystic fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic interstitial pneumonia (IIP) including idiopathic pulmonary fibrosis (IPF), chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplantation, premature rupture of membrane, bullosa, shock, sepsis, systemic lupus erythematodes (SLE), Crohn disease, disseminated intravascular coagulation (DIC), ischemia-reperfusion induced-tissue injury, corneal scar tissue formation, myelitis, lung squamous cell carcinoma, pulmonary adenocarcinoma, lung cancers such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colorectal cancer, skin cancer, pancreas cancer, glioma and the others.
    • MODE FOR CARRYING OUT THE INVENTION
  • Hereinafter, the compounds represented by formula (I) of the present invention are further explained.
  • A term “physiologically acceptable salts of compounds represented by formula (I)” means acid additional physiologically acceptable salts of compounds of formula (I) that contain any groups capable of forming acid addition salts in a structure thereof, or base additional physiologically acceptable salts of compounds of formula (I) that contain any groups capable of forming base addition salts in a structure thereof.
  • Specific examples of acid addition salts include salts with inorganic acids (such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate and phosphate); salts with organic acids (such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate and trifluoromethanesulfonate); as well as salts with amino acids (such as glutamate and aspartate). Specific examples of base addition salts include salts with alkali metal or alkaline-earth metals (such as sodium salt, potassium salt and calcium salt); salts with organic bases (such as pyridine salts and triethylamine salts); as well as salts with amino acids (such as lysine salts and arginine salts).
  • The compound of formula (I) and salts thereof may exist in forms of hydrates and/or solvates, and thus these hydrates and/or solvates may be also encompassed in the present compounds. That is to say, “Present compound” encompasses, in addition to the above-mentioned compounds of formula (I) and physiologically acceptable salts thereof, the hydrates and/or solvates thereof.
  • Also, the compound of formula (I) may contain one or more asymmetric carbon atoms and may form geometric isomer or axial chirality (i.e., atropisomer), and can thus exist as several kinds of stereoisomers. In the present invention, the compounds of formula (I) of the present invention encompass each of the stereoisomer, and mixtures and racemates thereof.
  • Also, the compounds of formula (I) may be labeled with one or more isotopes (such as 3H, 14C, 35S and so on). Also, the deuterium exchange product wherein any one or two or more 1H(s) is/are exchanged to 2H (D) in the compounds represented by formula (I) are also encompassed in the compounds represented by these general formulae respectively.
  • Herein, the number of substituents in the certain group defined by “(may be) optionally substituted” or “substituted” should not be specifically limited as long as the group can be substituted and includes, for example one to multiple. Also, when the number of the substituents is multiple, each of the substituents may be the same or different from each other. Specifically, the term “said aromatic ring group may be optionally substituted at one or more substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group” means, for example, that “said aromatic ring group is substituted at substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom or cyano group”, and the above-mentioned descriptions may be changed to “said aromatic ring group is substituted at substitutable positions with one or more same or different substituents selected from the group consisting of C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group and —NRcRd group. Also, the explanations for each group may apply to the case where the group is a part/moiety or a substituent of other group unless otherwise specified.
  • The terms described herein are explained below.
  • The term “alkyl” used herein means a straight or branched saturated hydrocarbon group, and the term “C1-3 alkyl”, “C1-6 alkyl” and “C1-10 alkyl” means an alkyl group having 1 to 3 carbon atoms, 1 to 6 carbon atoms, or 1 to 10 carbon atoms respectively. For specific examples thereof, examples of “C1-3 alkyl group” include methyl, ethyl, propyl, isopropyl and the others, examples of “C1-6 alkyl group” include in addition to the above-mentioned groups, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the others, and examples of “C1-10 alkyl group” include in addition to the above-mentioned groups, octyl, nonyl, decyl and the others, and said alkyl may be straight or branched. Preferably, examples of “C1-3 alkyl group” include methyl, ethyl, propyl and isopropyl, examples of “C1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, and examples of “C1-10 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl and nonyl.
  • The alkyl part of “C1-6 alkylthio” used herein is the same as defined in the above-mentioned “C1-6 alkyl”, and specific examples of “C1-6 alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, tert-butylthio and the others, and preferably include methylthio and ethylthio.
  • The alkyl part of “C1-6 alkylcarbonyl” used herein is the same as defined in the above-mentioned “C2-6 alkyl”, and specific examples of “C1-6 alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, tert-butylcarbonyl (pivaloyl) and the others, and preferably include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl.
  • The term “C3-6 cycloalkyl” used herein means a ring saturated or unsaturated hydrocarbon group having 3 to 6 carbon atoms, preferably means ring saturated hydrocarbon group, and include, for example, cyclopentene, cyclohexene, cyclopropane, cyclobutane, cyclopentane and cyclohexane. Preferred examples thereof include cyclopropane, cyclobutane and cyclopentane.
  • The term “C3-6 saturated carbocycle” used herein a ring saturated hydrocarbon group having 3 to 6 carbon atoms, and include cyclopropane, cyclobutane, cyclopentane and cyclohexane. Preferred examples thereof include cyclopropane, cyclobutane and cyclopentane.
  • The “C2-6 alkene group” used herein means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms, and include ethene, 1-propylene, 2-propylene, isopropylene, 1-butene, 2-butene, 3-butene, 1-pentene, 2-pentene, 3-pentene, 4-pentene, 1-hexene, 2-hexene, 3-hexene, 4-hexene, 5-hexene, 2-methyl-3-butene, 2-methyl-2-pentene, 3-methyl-2-pentene and the others. Preferred examples thereof include ethene, 2-propylene and 2-butene.
  • The term “halogen atom” used herein include fluorine atom, chlorine atom, bromine atom and iodine atom. Preferred examples thereof include fluorine atom, chlorine atom and bromine atom.
  • The term “alkoxy” used herein means a group wherein the alkyl group is attached to an oxygen atom, and the “alkyl” part is the same as defined in the above-mentioned “alkyl”. Specific examples of the “C1-3 alkoxy group” include methoxy, ethoxy, n-propoxy and isopropoxy, and specific examples of the “C1-6 alkoxy” include in addition to the above-mentioned groups, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy hexyloxy and the others. Preferred examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • The term “C1-6 alkoxycarbonyl” used herein means a group wherein the C1-6 alkoxy group is attached to a carbonyl group, and specific examples of the “C1-6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the others, and preferably include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • The term “five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S” used herein means a phenyl group and a mono-ring five to six-membered aromatic heteroring group consisting of carbon atoms as well as one to three heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Specific examples thereof include phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, pyridazinyl, triazolyl and the others. Preferred examples thereof include phenyl, pyridyl, pyrazinyl and triazolyl.
  • The term “five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S” used herein means a phenyl group and a mono-ring five to six-membered aromatic heteroring group consisting of carbon atoms as well as one to four heteroatoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Specific examples thereof include in addition to the above-mentioned specific examples for “five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S”, tetrazolyl and the others. Preferred examples thereof include phenyl, pyridyl, pyrazinyl and triazolyl.
  • The “six-membered aromatic ring group optionally containing one to four nitrogen atoms” used herein means a phenyl group and a mono-ring six-membered aromatic heteroring group consisting of carbon atoms as well as one to four nitrogen atoms, and specific examples thereof include phenyl, pyridyl, pyrimidinyl, triazinyl, tetrazinyl and the others. Preferred examples thereof include phenyl and pyridyl.
  • The term “six-membered aromatic ring group optionally containing one to two nitrogen atoms” used herein means a phenyl group and a mono-ring six-membered aromatic heteroring group consisting of carbon atoms as well as one to two nitrogen atoms, and specific examples thereof include phenyl, pyridyl and pyrimidinyl. Preferred specific examples thereof include phenyl and pyridyl.
  • The term “three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S” used herein means a mono-ring saturated hydrocarbon aliphatic ring group having three to six carbon atoms, as well as a mono-ring saturated heteroaliphatic ring group containing one to two same or different atoms selected from nitrogen atom, oxygen atom and sulfur atom. The above-mentioned nitrogen atom, oxygen atom and sulfur atom are all ring-constituting atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazolidinyl, tetrahydrofuranyl and the others. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl and tetrahydrofuranyl.
  • The term “four to six-membered unsaturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S” used herein means a mono-ring unsaturated hydrocarbon aliphatic ring group having four to six carbon atoms, as well as a four to six-membered unsaturated heteroaliphatic ring group containing one to two same or different atoms selected from nitrogen atom, oxygen atom and sulfur atom. The above-mentioned nitrogen atom, oxygen atom and sulfur atom are all ring-constituting atoms. Specific examples thereof include cyclobutenyl, cyclopentenyl, cyclohexenyl, dihydropyranyl, dihydrofuranyl, pyrrolinyl, imidazolinyl, pyrazolynlyl, oxazolinyl, thiazolinyl, dihydropyridinyl, tetrahydropyridinyl and the others. Preferred specific examples thereof include cyclobutenyl, cyclopentenyl, dihydropyranyl and tetrahydropyridyl.
  • The term “combine each other together with N (nitrogen atom) to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent four to six-membered saturated aliphatic ring group” used herein means a formation of a four to six-membered saturated heteroaliphatic ring group containing one nitrogen atom and optionally containing further one to two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Specific examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and the others. Preferred examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
  • The term “combine each other together with nitrogen atom to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent four to six-membered unsaturated aliphatic ring group” used herein means a formation of a four to six-membered unsaturated heteroaliphatic ring group containing one nitrogen atom and optionally containing further one to two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Specific examples thereof include tetrahydropyridyl, dihydropyrrolyl and the others. Preferred examples thereof include tetrahydropyridyl.
  • The term “three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O” used herein means a mono-ring saturated hydrocarbon aliphatic ring group having three to six carbon atoms as well as a three to six-membered saturated heteroaliphatic ring group containing one to two heteroatoms selected from nitrogen atom and oxygen atom. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the others. Preferred examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
  • The term “saturated aliphatic ring group substituted with alkyl group” used herein means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkyl group. Specific examples thereof include dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylazetidinyl, methylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl, ethylpiperazinyl, propylmorpholinyl and the others. Preferred examples thereof include dimethylcyclobutyl, dimethylcyclopentyl, methylazetidinyl, methylpyrrolidinyl, methylpiperidinyl, methylpiperazinyl, ethylpiperazinyl, propylmorpholinyl and the others.
  • The term “unsaturated aliphatic ring group substituted with alkyl group” used herein means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkyl group. Specific examples thereof include methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, methyltetrahydropyridyl, ethyltetrahydropyridyl, propyltetrahydropyridyl and the others. Preferred examples thereof include methylcyclopentenyl, methyltetrahydropyridyl, ethyltetrahydropyridyl and the others.
  • The term “combine each other together with nitrogen atom to which they are attached and optionally together with further oxygen atom to represent four to six-membered saturated aliphatic ring group” used herein means a formation of a four to six-membered saturated heteroaliphatic ring group containing one nitrogen atom and optionally containing further one or more oxygen atoms. Specific examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and the others. Preferred examples thereof include azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
  • The term “alkyl group substituted with halogen atom” used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atoms. Specific examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1-methyl-2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl and the others. Preferred examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 1,1-difluoroethyl
  • The term “alkoxy group substituted with halogen atom” used herein means the above-mentioned alkoxy group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atom. Specific examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1-difluoroethoxy, 1-methyl-2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, chloromethoxy, chloroethoxy, chloropropoxy, chlorobutoxy, bromoethoxy, bromopropoxy, bromobutoxy, iodoethoxy, iodopropoxy, iodobutoxy and the others. Preferred examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and 1,1-difluoroethoxy.
  • The term “alkylthio group substituted with halogen atom” used herein means the above-mentioned alkylthio group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atoms. Specific examples thereof include trifluoromethylthio, 2,2,2-trifluoroethylthio, 2-fluoroethylthio, 3-fluoropropylthio, 3,3,3-trifluoropropylthio and the others. Preferred examples include trifluoromethylthio and 2,2,2-trifluoroethylthio.
  • The term “alkylcarbonyl group substituted with halogen atom” used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with halogen atoms. Specific examples thereof include trifluoromethylcarbonyl, 2-fluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 3,3,3-trifluoropropylcarbonyl and the others. Preferred examples thereof include trifluoromethylcarbonyl, 2-fluoroethylcarbonyl and 2,2,2-trifluoroethylcarbonyl.
  • The term “alkoxycarbonyl group substituted with halogen atom” used herein means the above-mentioned alkoxycarbonyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atom are substituted with halogen atoms. Specific examples thereof include trifluoromethoxycarbonyl, 2-fluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 3,3,3-trifluoropropoxycarbonyl and the others. Preferred examples thereof include trifluoromethoxycarbonyl, 2-fluoroethoxycarbonyl and 2,2,2-trifluoroethoxycarbonyl.
  • The term “aromatic ring group substituted with halogen atom” used herein means the above-mentioned aromatic ring group substituted with one to three substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and iodine atom.
  • The term “saturated aliphatic ring group substituted with halogen atom” used herein means a mono-ring saturated aliphatic ring group substituted with one to three substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and iodine atom. Specific examples thereof include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, chlorocyclobutyl, dichlorocyclobutyl, fluorocyclopentyl, difluorocyclopentyl, chlorocyclopentyl, fluorocyclohexyl, difluorocyclohexyl, fluoroazetidinyl, difluoroazetidinyl, difluoropyrrolidinyl, difluoropiperidinyl, difluoromorpholinyl and the others. Preferred examples thereof include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, difluorocyclopentyl, difluoroazetidinyl and difluoropyrrolidinyl.
  • The term “unsaturated aliphatic ring group substituted with halogen atom” used herein means a mono-ring four to six-membered unsaturated aliphatic ring group substituted with one to three substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom and iodine atom. Specific examples thereof include fluorocyclobutenyl, difluorocyclobutenyl, chlorocyclobutenyl, dichlorocyclobutenyl, fluorocyclopentenyl, difluorocyclopentenyl, chlorocyclopentenyl, fluorocyclohexenyl, difluorocyclohexenyl, difluorotetrahydropyridyl and the others. Preferred examples include fluorocyclobutenyl, difluorocyclobutenyl and difluorocyclopentenyl.
  • The term “alkyl group substituted with hydroxy group” used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to five, preferably one to three) hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 2,5-dihydroxypentyl, 3,5-dihydroxypentyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl, 2,6-dihydroxyhexyl, 3,6-dihydroxyhexyl, 4,6-dihydroxyhexyl, 2-hydroxyisopropyl, 2-hydroxysec-butyl, 3-hydroxy-sec-butyl, 2-hydroxy-tert-butyl, 3-methyl-5-hydroxypentyl, 3-methyl-3-hydroxypentyl, 4-methyl-5-hydroxypentyl, 4-methyl-4-hydroxypentyl, 4-methyl-3-hydroxypentyl and the others. Preferred examples thereof include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 1-hydroxy-2-propyl, 3-hydroxypropyl and 1,3-dihydroxy-2-propyl.
  • The term “alkoxy group substituted with hydroxy group” used herein means the above-mentioned alkoxy group wherein one, two or more (for example, one to five, preferably one to two) hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 1,3-dihydroxypropoxy, 2,3-dihydroxypropoxy, 2-hydroxybutoxy, 3-hydroxybutoxy, 4-hydroxybutoxy, 2,3-dihydroxybutoxy, 3,4-dihydroxybutoxy, 2,4-dihydroxybutoxy, 2-hydroxypentyloxy, 3-hydroxypentyloxy, 4-hydroxypentyloxy, 5-hydroxypentyloxy, 2,5-hydroxypentyloxy, 3,5-hydroxypentyloxy, 2-hydroxyhexyloxy, 3-hydroxyhexyloxy, 4-hydroxyhexyloxy, 5-hydroxyhexyloxy, 6-hydroxyhexyloxy, 2,6-dihydroxyhexyloxy, 3,6-dihydroxyhexyloxy, 4,6-dihydroxyhexyloxy, 1-hydroxy-2-propoxy, 2-hydroxy-2-butoxy, 3-hydroxy-2-butoxy, 3-methyl-5-hydroxypentyloxy, 3-methyl-3-hydroxypentyloxy, 4-methyl-5-hydroxypentyloxy, 4-methyl-4-hydroxypentyloxy, 4-methyl-3-hydroxypentyloxy and the others. Preferred examples thereof include 2-hydroxyethoxy, 2-hydroxypropoxy, 1-hydroxy-2-propoxy, 3-hydroxypropoxy and 1,3-dihydroxy-2-propoxy.
  • The term “alkylthio group substituted with hydroxy group” used herein means the above-mentioned alkylthio group wherein one, two or more (for example, one to five, preferably one to two hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include 2-hydroxyethylthio, 2-hydroxy-1-propylthio, 3-hydroxy-1-propylthio, 1-hydroxy-2-propylthio and the others. Preferred examples thereof include 2-hydroxyethylthio, 3-hydroxy-1-propylthio and 1-hydroxy-2-propylthio.
  • The term “alkylcarbonyl group substituted with hydroxy group” used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to five, preferably one to two hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, hydroxyisopropylcarbonyl, hydroxybutylcarbonyl and the others. Preferred examples thereof include hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl and hydroxybutylcarbonyl.
  • The term “alkoxycarbonyl group substituted with hydroxy group” used herein means the above-mentioned alkoxycarbonyl group wherein one, two or more (for example, one to five, preferably one to two hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxyethoxycarbonyl, hydroxypropoxycarbonyl, hydroxyisopropoxycarbonyl, hydroxybutoxycarbonyl and the others. Preferred examples thereof include hydroxyethoxycarbonyl, hydroxypropoxycarbonyl and hydroxyisopropoxycarbonyl.
  • The term “aromatic ring group substituted with hydroxy group” used herein means the above-mentioned aromatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with hydroxy groups.
  • The term “saturated aliphatic ring group substituted with hydroxy group” used herein means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, hydroxyazetidinyl, hydroxypyrrolidinyl, hydroxypiperidinyl and the others. Preferred examples thereof include hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxyazetidinyl and hydroxypyrrolidinyl.
  • The term “unsaturated aliphatic ring group substituted with hydroxy group” used herein means the above-mentioned unsaturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with hydroxy groups. Specific examples thereof include hydroxycyclobutenyl, hydroxycyclopentenyl, hydroxycyclohexenyl, hydroxytetrahydropyridyl and the others. Preferred examples thereof include hydroxycyclopentenyl and hydroxycyclohexenyl.
  • The term “aromatic ring group substituted with alkyl group” used herein means the above-mentioned aromatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with alkyl groups.
  • The term “aromatic ring group substituted with cyano group” used herein means the above-mentioned aromatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups.
  • The term “alkyl group substituted with cyano group” used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, cyanobutyl, cyanoisobutyl, cyanopentyl, cyanohexyl, cyanooctyl, cyanononyl, cyanodecyl and the others. Preferred examples thereof include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 1-cyano-2-propyl and 4-cyanobutyl.
  • The term “alkoxy group substituted with cyano group” means the above-mentioned alkoxy group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include cyanomethoxy, cyanoethoxy, cyanopropoxy, cyanoisopropoxy, cyanobutoxy, cyanopentyloxy, cyanohexyloxy, cyanooctyloxy, cyanononyloxy, cyanodecyloxy and the others. Preferred examples thereof include cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 1-cyano-2-propoxy and 4-cyanobutoxy.
  • The term “alkylthio group substituted with cyano group” used herein means the above-mentioned alkylthio group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include 2-cyanoethylthio, 2-cyano-1-propylthio, 3-cyano-1-propylthio, 1-cyano-2-propylthio and the others. Preferred examples thereof include 2-cyanoethylthio, 3-cyano-1-propylthio and 1-cyano-2-propylthio.
  • The term “alkylcarbonyl group substituted with cyano group” used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl, cyanoisopropylcarbonyl, cyanobutylcarbonyl, cyanopentylcarbonyl, cyanohexylcarbonyl and the others. Preferred examples thereof include cyanomethylcarbonyl, cyanoethylcarbonyl, cyanopropylcarbonyl, cyanoisopropylcarbonyl and cyanobutylcarbonyl.
  • The term “saturated aliphatic ring group substituted with cyano group” used herein means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include cyanocyclobutyl, cyanocyclopentyl, cyanocyclohexyl, cyanopyrrolidinyl, cyanopiperidinyl, cyanopiperazinyl, cyanomorpholinyl, cyanotetrahydrofuranyl and the others. Preferred examples thereof include cyanocyclobutyl, cyanocyclopentyl, cyanocyclohexyl, cyanopyrrolidinyl and cyanopiperidinyl.
  • The term “unsaturated aliphatic ring group substituted with cyano group” used herein means the above-mentioned unsaturated aliphatic ring group wherein one, two or more (for example, one to two) hydrogen atoms are substituted with cyano groups. Specific examples thereof include cyanocyclobutenyl, cyanocyclopentenyl, cyanocyclohexenyl, cyanodihydropyranyl, cyanodihydrofuranyl, cyanodihydropyridyl, cyanotetrahydropyridyl and the others. Preferred examples thereof include cyanocyclopentenyl, cyanocyclohexenyl, cyanodihydropyridyl and cyanotetrahydropyridyl.
  • The term “alkyl group substituted with alkoxy group” used herein means the above-mentioned alkyl group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups. Specific examples thereof include methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, isopropoxypropyl, methoxyisopropyl, ethoxyisopropyl, propoxyisopropyl, isopropoxyisopropyl, methoxybutyl, ethoxybutyl, propoxybutyl, isopropoxybutyl, methoxyisobutyl, ethoxyisobutyl, propoxyisobutyl, isopropoxyisobutyl and the others. Preferred examples thereof include methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, methoxypropyl and ethoxypropyl.
  • The term “aromatic group substituted with alkoxy group” means the above-mentioned aromatic group wherein one, two or more (for example, one to three) hydrogens are substituted with the above-mentioned alkoxy groups.
  • The term “alkylcarbonyl group substituted with alkoxy group” used herein means the above-mentioned alkylcarbonyl group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups. Specific examples thereof include methoxymethylcarbonyl, ethoxymethylcarbonyl, methoxyethylcarbonyl, ethoxyethylcarbonyl, methoxypropylcarbonyl, methoxyisopropylcarbonyl and the others. Preferred examples thereof include methoxymethylcarbonyl, ethoxymethylcarbonyl, methoxyethylcarbonyl and ethoxyethylcarbonyl.
  • The term “saturated aliphatic ring group substituted with alkoxy group” means the above-mentioned saturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups. Specific examples thereof include methoxycyclopropyl, ethoxycyclopropyl, methoxycyclobutyl, ethoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl, methoxytetrahydropyranyl, methoxypyrrolidinyl, methoxypiperidinyl, methoxytetrahydrofuranyl, methoxyazetidinyl, ethoxyazetidinyl, methoxypyrrolidinyl, ethoxypyrrolidinyl, methoxypiperidinyl and the others. Preferred examples thereof include methoxycyclopropyl, ethoxycyclopropyl, methoxycyclobutyl, ethoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl and methoxyazetidinyl.
  • The term “unsaturated aliphatic ring group substituted with alkoxy group” used herein means the above-mentioned unsaturated aliphatic ring group wherein one, two or more (for example, one to three) hydrogen atoms are substituted with the above-mentioned alkoxy groups. Specific examples thereof include methoxycyclobutenyl, methoxycyclopentenyl, methoxycyclohexenyl, ethoxycyclobutenyl, ethoxycyclopentenyl, ethoxycyclohexenyl, methoxydihydropyranyl, methoxydihydrofuranyl, methoxytetrahydropyridinyl and the others.
  • The term “alkyl group substituted with optionally substituted aromatic ring group” used herein means the above-mentioned alkyl group wherein one, two or more hydrogen atoms are substituted with “optionally substituted aromatic ring group”. Specific examples thereof include an alkyl group having one to six carbon atoms wherein any hydrogen atoms are substituted with optionally substituted aromatic ring groups such as phenyl, pyridyl, oxazolyl, thiazolyl and pyrazolyl. Specific examples of substituents of said optionally substituted aromatic ring group include methoxy, methanesulfonyl, dimethylamino, cyano and the others.
  • The term “alkoxy group substituted with optionally substituted aromatic ring group” used herein means a group wherein the above-mentioned “alkyl group substituted with optionally substituted aromatic ring group” is attached to an oxygen atom.
  • The term “alkylthio group substituted with optionally substituted aromatic ring group” used herein means a group wherein the above-mentioned alkyl group substituted with optionally substituted aromatic ring group is attached to a sulfur atom.
  • The term “saturated aliphatic ring group substituted with oxo group” used herein means the above-mentioned saturated aliphatic ring group wherein one to two hydrogen atoms are replaced with oxo groups. Specific examples thereof include 2-oxocyclopentyl, 3-oxocyclopentyl, 2-oxocyclohexyl, 3-oxocyclohexyl, 4-oxocyclohexyl, 2-oxopyrrolidinyl, 3-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, 2-oxopiperidinyl, 3-oxopiperidinyl, 4-oxopiperidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, 2-oxomorpholinyl, 2-oxothiomorpholinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxazolidinyl, dioxazolidinyl, dioxothiazolidinyl and the others. Preferred examples thereof include 4-oxocyclohexyl, 2-oxopyrrolidinyl, 3-oxopyrrolidinyl, 2-oxopiperazinyl and 3-oxopiperazinyl.
  • The term “unsaturated aliphatic ring group substituted with oxo group” used herein means the above-mentioned unsaturated aliphatic ring group wherein one to two oxo hydrogen atoms are replaced with oxo groups. Specific examples thereof include oxocyclopentenyl, oxocyclohexenyl, oxopyrrolinyl, oxoimidazolinyl, oxo-oxazolidinyl, oxothiazolinyl, oxodihydropyridinyl, oxotetrahydropyridinyl and the others. Preferred examples thereof include oxopyrrolinyl, oxoimidazolinyl, oxodihydropyridinyl and oxotetrahydropyridinyl.
  • Any groups other than the above-mentioned groups are defined and exemplified similarly to the above-mentioned exemplification. Also, the term “aliphatic ring group” means an alicyclic group.
  • Each group used herein is explained.
  • Hereinafter, any groups described in formula (I) are explained.
  • Ra represents a hydrogen atom or a C1-6 alkyl optionally substituted with hydroxy group or halogen atom, preferably a hydrogen atom or a C1-3 alkyl group optionally substituted with hydroxy group or fluorine atom, and more preferably a hydrogen atom, methyl, ethyl, trifluoromethyl, difluoromethyl, hydroxymethyl or hydroxyethyl.
  • Rb represents a hydrogen atom, a C1-6 alkyl optionally substituted with hydroxy group or halogen atom, a benzyl group optionally substituted with methoxy group or nitro group or a C3-6 cycloalkyl group optionally substituted with hydroxy group or halogen atom, preferably a hydrogen atom, a C1-6 alkyl group optionally substituted with hydroxy group or halogen atom or a benzyl group optionally substituted with methoxy group or nitro group, and more preferably a hydrogen atom or a C1-3 alkyl group optionally substituted with hydroxy group or fluorine atom.
  • Also, Rb represents preferably a C1-6 alkyl group optionally substituted with hydroxy group or halogen atom, more preferably a C1-3 alkyl group optionally substituted with hydroxy group or fluorine atom.
  • Rb2 represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NRaRb or halogen atom), a benzyl group (said benzyl group may be optionally substituted with methoxy group or nitro group) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or halogen atom), preferably a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NRaRb or fluorine atom) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom), more preferably a hydrogen atom or a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or —NRaRb).
  • Rb3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or halogen atom) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or halogen atom), preferably a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom), and more preferably a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group).
  • Rb4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or halogen atom), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or halogen atom) or an 2-isopropyl-5-methylcyclohexyl, preferably a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom) or an 2-isopropyl-5-methylcyclohexyl, more preferably a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom), further more preferably a C1-6 alkyl group (said alkyl group may be optionally hydroxy group) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group).
  • Rc and Rd represent independently of each other a hydrogen atom, or a C1-3 alkyl group optionally substituted with an C1-3 alkoxy group, cyano group, hydroxy group or halogen atom, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb, —NRaC(═O)ORh, or NRaC(═O)Rh), C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, halogen atom or oxo group), preferably Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group optionally substituted with hydroxy group or fluorine atom, or alternatively combine each other together with one to two heteroatoms independently selected from the group consisting of N and O to represent a four to six-membered saturated heteroaliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group, hydroxy group, fluorine atom or oxo group), and more preferably Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group optionally substituted with hydroxy group or fluorine atom, or alternatively combine each other to represent a saturated heteroaliphatic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine and morpholine (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group, hydroxy group or fluorine atom),
  • also, preferably, Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with C1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb, —NRaC(═O)ORh or —NRaC(═O) Rh), C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, fluorine atom or oxo group),
  • more preferably, Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with methoxy, cyano, hydroxy or fluorine) or alternatively combine each other to represent a saturated heteroaliphatic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine and morpholine (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb or —NRaC(═O)Rh), methoxy group, —NRaRb group, —NRaC(═O)Rh group, hydroxy group, fluorine atom or oxo group).
  • Rc2 and Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or halogen atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group, C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, halogen atom or oxo group),
  • preferably, Rc2 and Rd2 represent independently of each other to represent a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group, C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, fluorine atom or oxo group),
  • more preferably, Rc2 and Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with —NRaRb, —NRaC(═O)Rh, methoxy, cyano, hydroxy or fluorine) or alternatively combine each other to represent a saturated heteroaliphatic ring group selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, morpholine, oxazolidine and imidazolidine (said aliphatic ring group may be optionally substituted at substitutable positions with methoxy, —NRaRb, —NRaC(═O)Rh, hydroxy, fluorine or oxo).
  • Re represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group), an -A group, a —C(═O)-A group, a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy group, halogen atom, cyano group, C1-3 alkoxy group or —NRcRd group), a C1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy group or halogen atom), —C(═O)NRcRd group or —S(═O)mRb group,
  • preferably, represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, fluorine atom, C1-3 alkoxy group, or —NRcRd group), an -A group, a —C(═O)-A group, a C1-6 alkylcarbonyl group (the alkyl moiety of the alkylcarbonyl group may be optionally substituted with hydroxy group or halogen atom), a —C(═O)NRcRd group or a —S(═O)mRb group,
  • more preferably, represent a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), an -A group, a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy group or fluorine atom) or a —S(═O)2Rb group.
  • Rf represents a hydrogen atom, a hydroxy group, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom group, C1-3 alkoxy group or —NRcRd group), a C1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group), an -A group or a —NRaRi group; preferably, represents a hydrogen atom, a hydroxy group, a C1-3 alkyl group, a C1-3 alkoxy group, an -A group or a —NRaRi group; and more preferably, represents a hydroxy group, an -A group or a —NRaRi group.
  • Rg represents a hydroxy group, a chlorine atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group), an -A group or a —NRaRi group; preferably, represents a chlorine atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group or fluorine atom), an -A group or a —NRaRi group; and more preferably, represents a C1-3 alkyl group (said alkyl group may be optionally substituted with cyano group or fluorine atom), an -A group or a —NRaRi group.
  • Also, Rg represents preferably a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom, or —NRcRd group), a chlorine atom, an -A group or a —NRaRi group.
  • Rg2 represents a hydroxy group, a chlorine atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group) or an -A group; preferably represents a hydroxy group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a chlorine atom or an -A group; and more preferably represents a hydroxy group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom).
  • Rg3 represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group) or an -A group; preferably represent a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom or —NRcRd group).
  • Rh represents a C1-6 alkyl group optionally substituted with hydroxy group or halogen atom, preferably a C1-3 alkyl group optionally substituted with hydroxy group or fluorine atom, and more preferably methyl, ethyl or trifluoroethyl.
  • Ri represents a hydrogen atom or a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, halogen atom, C1-3 alkoxy group, C3-6 cycloalkyl group or —NRcRd group), an -A group, a —C(═O)Rb group, a —C(═O)Rh group, a —C(═O)A group or a C1-6 alkylcarbonyl group (the alkyl moiety of the alkylcarbonyl group may be optionally substituted with hydroxy group, halogen atom, cyano group, C1-3 alkoxy group or —NRcRd group); preferably represents a hydrogen atom or a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, cyano group, fluorine atom, C1-3 alkoxy group, C3-6 cycloalkyl group or —NRcRd group) or an -A group; more preferably represent a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, C1-3 alkoxy group or fluorine atom) or an -A group.
  • A represents a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group) or a three to six-membered saturated or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or an oxo group),
  • preferably, represents an optionally substituted aromatic ring group selected from the group consisting of phenyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (said aromatic ring group may be optionally substituted with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group) or an optionally substituted saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, pyrrolinyl, dihydropyridinyl and tetrahydropyridinyl (said aliphatic ring group may be optionally substituted with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group), and
  • more preferably, represents aromatic heteroring group selected from the group consisting of imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl (said aromatic heteroring group may be optionally substituted with C1-3 alkyl group optionally substituted with hydroxy or fluorine, C1-3 alkoxy group optionally substituted with hydroxy or fluorine, hydroxy group, fluorine atom, cyano group, —C(═O)OH group or —NRcRd group) or a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (said aliphatic ring group may be optionally substituted with C1-3 alkyl group optionally substituted with hydroxy or fluorine, C1-3 alkoxy group optionally substituted with hydroxy or fluorine, hydroxy group, fluorine atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group),
  • further more preferably represents a saturated aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl and piperidinyl (said aliphatic ring group may be optionally substituted with C1-3 alkyl group optionally substituted with hydroxy or fluorine, C1-3 alkoxy group optionally substituted with hydroxy or fluorine atom, hydroxy group, fluorine atom, cyano group, —C(═O)OH group or —NRcRd group).
  • Also, preferably, A represents an aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine), or
  • an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group, C1-3 alkoxy group, hydroxy group, fluorine atom, —NRcRd or oxo group).
  • Preferred one embodiment with respect to a combination of the above-mentioned each group include the followings:
  • Ra represents a hydrogen atom or a C1-6 alkyl group optionally substituted with hydroxy group or halogen atom;
  • Rb represents a C1-6 alkyl group optionally substituted with hydroxy group or halogen atom;
  • Rb2 represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NRaRb group or fluorine atom) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom);
  • Rb3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom);
  • Rb4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine atom or chlorine atom), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy group or fluorine atom) or a residue of menthol group;
  • Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with C1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to form a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, —NRaRb group, —NRaC(═O)ORh group, or NRaC(═O)Rh group), a C1-3 alkoxy group, a —NRaRb group, a —NRaC(═O)ORa group, a —NRaC(═O) Ra group, a —C(═O)ORa group, a hydroxy group, a fluorine atom or an oxo group);
  • Rc2 and Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to form a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group, C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, fluorine atom or oxo group);
  • Re represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), an -A group, a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy group or fluorine atom) or a —S(═O)2Rb group;
  • Rf represents a hydroxy group, an -A group or a —NRaRi group;
  • Rg represents a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom or —NRcRd group), a chlorine atom, an -A group or a —NRaRi group;
  • Rg2 represents a hydroxy group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group or fluorine atom), a chlorine atom or an -A group;
  • Rg3 represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom or —NRcRd group);
  • Rh represents a C1-3 alkyl group optionally substituted with hydroxy group or fluorine tom;
  • Ri represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy group, C1-3 alkoxy group or fluorine atom) or an -A group;
  • A represents
  • an aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy group or fluorine atom) or
  • an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group, C1-3 alkoxy group, hydroxy group, fluorine atom, —NRcRd group or oxo group); and
  • m is an integer of 1 or 2.
  • R1 represents a hydrogen atom, a C1-10 alkyl group, a C2-6 alkene group, or a three to six-membered saturated- or four- to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • wherein said alkyl group and said alkene group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 1:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkoxy group (said alkoxy group may be optionally substituted with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (7) three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, cyano, —NRaC(═O)Rb, —NRaC(═O)NRcRd, —NRaS(═O)mRb, —C(═O)ORb, —C(═O)NRcRd or —NRcRd),
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —C(O)Rb,
      • —S(═O)mNRcRd,
      • —S(═O)mRb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (9) —OC(═O)NRcRd group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group,
  • (12) thiol group,
  • (13) nitro group and
  • (14) —ORe group,
  • wherein said saturated or unsaturated aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 2:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRaRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (6) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (8) three- to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb group,
      • —NRaS(═O)mRb group,
      • —C(═O)ORb group,
      • —C(═O)NRcRd group,
      • —NRcRd group or
      • oxo group),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group,
  • (13) thiol group,
  • (14) oxo group,
  • (15) nitro group,
  • (16) —NRaC(═O)Rb group,
  • (17) —NRaC(═O)NRcRd group,
  • (18) —NRaS(═O)mRb group,
  • (19) —C(═O)ORb group and
  • (20) —C(═O)NRcRd group,
  • R1 represents preferably a C1-10 alkyl group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • wherein
  • said alkyl group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (14) of Substituent List 1,
  • said saturated or unsaturated aliphatic ring group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (20) of Substituent List 2,
  • R1 represents more preferably a C1-10 alkyl group or a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
  • wherein
  • said alkyl group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (4) and (6) to (10) of Substituent List 1,
  • said saturated aliphatic ring group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of (1) to (4), (7) to (12), (14), (19) and (20) of Substituent List 2,
  • R1 represents further more preferably
  • a C1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of the followings:
  • (1) hydroxy group,
  • (2) fluorine atom,
  • (3) cyano group,
  • (4) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or fluorine,
      • C1-3 alkoxy group optionally substituted with hydroxy or fluorine,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)OH,
      • —C(═O)NRcRd or
      • —NRcRd),
  • (6) five-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or fluorine,
      • C1-3 alkoxy group optionally substituted with hydroxy or fluorine,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —C(═O)OH,
      • —C(═O)NRcRd or
      • —NRcRd),
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy group, fluorine atom, cyano, —C(═O)OH group or —C(═O)NRcRd),
      • C1-3 alkoxy group optionally substituted with hydroxy or fluorine,
      • hydroxy group,
      • fluorine atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaC(═O)NRcRd,
      • —NRaS(═O)mRb,
      • —C(═O)OH,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group and
  • (10) —C(═O)Rf group),
  • or
    a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted at substitutable positions with one substituent or multiple substituents less than three selected from the group consisting of the followings:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —S(═O)mNRcRd,
      • —S(═O)mRb or
      • —NRcRd),
  • (8) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —NRcRd or
      • oxo group),
  • (9) —NRaRe group,
  • (10) —OC(═O)NRcRd group,
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group,
  • (14) oxo group,
  • (19) —C(═O)ORb group and
  • (20) —C(═O)NRcRd group).
  • Also, R1 represents preferably
  • a C1-10 alkyl group (said alkyl group may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
    • Substituent List 8:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
      • C1-3 alkyl group optionally substituted with hydroxy or halogen,
      • C1-3 alkoxy group optionally substituted with hydroxy or halogen,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • —NRaC(═O)Rb,
      • —NRaS(═O)mRb,
      • —C(═O)ORb,
      • —C(═O)NRcRd,
      • —C(═O)Rb,
      • —NRcRd or
      • oxo group),
  • (8) —NRaRe group,
  • (10) —C(═O)Rf group,
  • (11) —S(═O)mRg group and
  • (12) thiol group) or
  • a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 9:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (3) cyano group,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions,
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
  • (5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
      • hydroxy group,
      • halogen atom,
      • cyano group,
      • five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with an C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
      • three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group)),
  • (11) —C(═O)Rf group,
  • (12) —S(═O)mRg group and
  • (14) oxo group.
  • R1 represents more preferably
  • a C1-10 alkyl group (said alkyl may be optionally substituted at substitutable positions with one to three substituents selected from the group consisting of
    • Substituent List 10:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, —C(═O)ORb group, —C(═O)NRcRd group, —C(═O)Rb group or oxo group),
  • (8) —NRaRe group and
  • (11) S(═O)2Rg group) or
  • a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
    • Substituent List 11:
  • (1) hydroxy group,
  • (2) halogen atom,
  • (4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with hydroxy or halogen),
  • (9) —NRaRe group,
  • (11) —C(═O)Rf group, and
  • (14) oxo group).
  • R2 represents a hydrogen atom, a halogen atom, a cyano group, a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra).
  • R2 represents preferably a —NRcRd group, a —N═CHN(CH3)2 group or a C2-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra).
  • R2 represents more preferably a hydrogen atom, an amino group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra), and represents further more preferably a hydrogen atom, an amino group, a methyl group or a hydroxymethyl group.
  • m represents an integer of one (1) or two (2) and preferably represents 2.
  • n represents an integer of zero (0) to two (2) and preferably represents 2.
  • L represents a six-membered aromatic ring group optionally containing one to four nitrogen atoms (said group may be optionally substituted at substitutable positions with halogen, —C(═O)NRcRd, —C(═O)ORa, hydroxy, —NRcRd, nitro, —NRaC(═O)Rb, C1-6 alkyl or C2-6 alkene, wherein said alkyl and said alkene may be optionally substituted independently of each other with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa), a Pyr-1 of the following formula, a Tri-1 of the following formula or an Imi-1 of the following formula:
  • Figure US20140179670A1-20140626-C00019
  • (in each formula, bond 1 represents a binding to uracil ring, bond 2 represents a binding to Ar2, and Z1, Z2 and Z3 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, —C(═O)ORb2 group, —CHO group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rh group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a —S—Rg3 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, an C1-6 alkyl group or a C2-6 alkene group, wherein said alkyl group and said alkene group may be optionally substituted independently of each other with halogen, hydroxy, —NRcRd, —C(═O)NRcRd, —NRaS(═O)mRh or —C(═O)ORa, and said saturated aliphatic ring group may be optionally substituted with hydroxy, halogen, C1-6 alkyl, C1-3 alkoxy, —C(═O)ORa, —C(═O)Ra or —NRaRb)).
  • Also, in one embodiment, in each formula, bond 1 represents a binding to uracil ring, bond 2 represents a binding to Ar2, and Z1, Z2 and Z3 may be optionally substituted independently of each other with halogen, —C(═O)NRcRd, —C(═O)ORa, nitro, hydroxy, —NRcRd, —NRaC(═O)Rb, hydrogen, C1-6 alkyl or C2-6 alkene, wherein said alkyl and said alkene may be optionally substituted independently of each other with halogen, hydroxy, —NRcRd, —C(═O)NRcRd or —C(═O)ORa).
  • Preferably, L represents
  • a six-membered unsubstituted aromatic ring group optionally containing one to two nitrogen atoms, a Pyr-1 of the following formula or a Tri-1 of the following formula:
  • Figure US20140179670A1-20140626-C00020
  • (in each formula, bond 1 represents a binding to uracil ring, bond 2 represents a binding to Ar2, and Z1 and Z2 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, —CHO group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rh group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a —S—Rg3 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted with hydroxy, halogen, C1-6 alkyl, C1-3 alkoxy, —C(═O)ORa, —C(═O)Ra or —NRaRb), a C1-6 alkyl group or a C2-6 alkene group (said alkyl group and said alkene group may be optionally substituted independently of each other with halogen, hydroxy, —NRcRd, —C(═O)NRcRd, —NRaS(═O)mRh, —C(═O)NRcRd or —C(═O)ORa)).
  • Preferably, Z1 and Z2 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —CHO group, a nitro group, a —NRaC(═O)Rb group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted with halogen, C1-6 alkyl, —C(═O)ORa or —C(═O)Ra), or a C1-6 alkyl group (said alkyl group may be optionally substituted with halogen, —C(═O)NRcRd, —NRaS(═O)mRh, —C(═O)NRcRd or —C(═O)ORa).
  • When L represents a six-membered aromatic ring group optionally containing one to four nitrogen atoms, preferred binding position on said aromatic ring represents a binding manner in which said uracil backbone and said Ar2 are attached to adjacent carbon atoms on the aromatic ring respectively as shown in the following formula (I′):
  • Figure US20140179670A1-20140626-C00021
  • and
  • L represents preferably a benzene ring group, a pyridine ring group, a group of formula Pyr-1, a group of formula Tri-1 or a group of formula Imi-1, and represents more preferably a benzene ring group, a pyridine ring group, a group of formula Pyr-1 or a group of formula Tri-1. Further more preferably, L represents a group of formula Pyr-1.
  • Ar1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or multiple substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
  • preferably, Ar1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions independently of each other with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group),
  • more preferably, Ar1 represents a benzene ring or a pyridine ring represented by the following formula Ar1-1:
  • Figure US20140179670A1-20140626-C00022
  • (in the formula, K1, K2, K3 and K4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, X represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K1 to K4 further with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group,
  • further preferably, Ar1 represents a group of the following formula Ar1-10:
  • Figure US20140179670A1-20140626-C00023
  • (in the formula, X represents a C1-3 alkyl group optionally substituted with one to three fluorine atoms, a chlorine atom, a cyano group or a nitro group).
  • Ar2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or multiple substitutable positions with C1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group, or —NRcRd group),
  • preferably, Ar2 represents a benzene ring or a pyridine ring represented by the following formula Ar2-1:
  • Figure US20140179670A1-20140626-C00024
  • (in the formula, L1, L2, L3 and L4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, Y represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L1 to L4 further with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group,
  • more preferably, Ar2 represents a structure wherein L2 position is unsubstituted or is substituted with C1-6 alkyl, C1-3 alkoxy, hydroxy, halogen or —S(═O)nRh,
  • further more preferably, Ar2 represents a group of the following formula Ar2-10:
  • Figure US20140179670A1-20140626-C00025
  • (in the formula, Y represents a cyano group, a chlorine atom or a nitro group).
  • One embodiment with respect to a preferred combination of Ar1 and Ar2 include the followings:
  • Ar1 represents the following formula Ar1-1:
  • Figure US20140179670A1-20140626-C00026
  • (in the formula, K1, K2, K3 and K4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, X represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K1 to K4 further with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group);
  • Ar2 represents the following formula Ar2-1:
  • Figure US20140179670A1-20140626-C00027
  • (in the formula, L1, L2, L3 and L4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, Y represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
  • said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L1 to L4 further with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group).
  • Examples of preferred compounds as uracil derivatives represented by formula (I) include the compounds wherein the formula (I) represents the following formula (I′″):
  • Figure US20140179670A1-20140626-C00028
  • (wherein,
  • Z1 represents a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a hydrogen atom, a —S(═O)2NRc2Rd2 group, a —S(═O)2NRaC(═O)Rb3 group, a —S(═O)2NRaC(═O)ORb4 group, a —S(═O)2NRaC(═O)NRaRb3 group or a S(═O)2Rg group,
  • X represents a C1-3 alkyl group optionally substituted with one or multiple fluorines or a nitro group, and
  • Y represents a cyano group, a chlorine atom or a nitro group)
  • or physiologically acceptable salts thereof.
  • The compounds or physiologically acceptable salts thereof wherein in the above-mentioned formula (I′″),
  • Z1 represents a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —S(═O)2NRc2Rd2 group, a —S(═O)2NRa2C(═O)Rb3 group, a —S(═O)2NRaC(═O)ORb4 group, a —S(═O)2NRaC(═O)NRaRb3 group, a S(═O))2Rg group, an iodine atom, a bromine atom or a chlorine atom, and
  • R2 represents a C1-3 alkyl group optionally substituted with hydroxy,
  • can exist as atropisomer.
    • Process of Present Compound
  • The Present compound represented by formula (I) or physiologically acceptable salts thereof is a novel compound, and can be prepared according to the below-mentioned processes, the below-mentioned examples or equivalent processes to known processes.
  • The compounds obtained by the below-mentioned processes may form salts thereof as long as they do not afford any adverse effect to an intended reaction.
    • [Process A]
  • The compounds of formula (I) is prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00029
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined above, and X1 represents halogen atoms (for example, chlorine atom, bromine atom and iodine atom) or an amino group)
    • [A-1]
  • When X1 in compound (IIa) represents a halogen atom, the compound (I) can be prepared by performing a coupling reaction on the compound (IIa) with Z1-L-Ar2 (wherein Z1 is a substituent on carbon atom in L ring and represents a metal substituent (for example, boronic acid, boronate ester, organotin, zinc halide, magnesium halide, organosilicon and lithium)) according to a conventional method. For example, the reaction can be achieved by performing a cross-coupling reaction on the compound (IIa) and Z1-L-Ar2 in appropriate solvents or under solvent-free condition in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium), copper catalysts (typically, copper iodide), nickel catalysts (typically, nickel chloride-1,2-bis(diphenylphosphino)ethane complex), zinc reagents, iron chelating reagents and the others, optionally with an addition of phosphorus ligands (typically, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphino biphenyl). Such coupling reactions may be carried out in the co-presence of alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example or potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali hydroxides (for example, sodium hydroxide) or metal alkoxides (for example, potassium t-butoxide) in addition to the above-mentioned reagents.
    • [A-2]
  • Also, when X1 in compound (IIa) represents a halogen atom, the compound (I) can be prepared by converting the X1 in compound (IIa) into coupling reactive group (for example, boronic acid group, zinc halide group, and magnesium halide group) followed by performing a coupling reaction on the resultant compounds with Z2-L-Ar2 (wherein Z2 is a substituent on carbon atom in L ring and represents a halogen atom) according to a conventional method. For example, this reaction can be achieved by reacting the compound (IIa) with boron reagents (typically, bis(pinacolato)diboron reagents) and palladium catalysts (typically, tetrakis(triphenylphosphin)palladium) to prepare boron compounds, by reacting the compound (IIa) with zinc dust and alkyl magnesium reagents to prepare zinc halides, or by reacting the compound (IIa) with magnesium powder to prepare magnesium halides, respectively in appropriate solvents or under solvent-free condition, followed by performing a cross-coupling reaction on the compound (IIa) with Z2-L-Ar2 in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium or bis(triphenylphosphine)palladium dichloride), copper catalysts (typically, copper iodide), nickel catalysts (typically, nickel chloride-1,2-bis(diphenylphosphino)ethane complex), zinc reagents, iron chelating reagents or the others, optionally with an addition of ligand compounds (for example, phosphorus ligands (typically, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphino biphenyl) or organoarsenic compounds). Such coupling reactions may be carried out in the co-presence of alkali metal carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example, potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali metal hydroxides (for example, sodium hydroxide) or metal alkoxides (for example, potassium t-butoxide) in addition to the above-mentioned reagents.
    • [A-3]
  • Also, when X1 in compound (IIa) represents an amino group, the compound (I) can be prepared by performing a cyclization of the compound (IIa) with Ar2's carbohydrazides (i.e., Ar2—C(═O)NHNH2) according to a conventional method. For example, the reaction can be achieved by reacting the compound (IIa) with Ar2's carbohydrazides in appropriate solvents or under solvent-free condition in the presence of N,N-dimethylformamide dimethyl acetal and acetic acid. For example, the compound (I) can be prepared, for example, according to the method described in Org. Lett. 2004, 17(6), 2969-2971 or the like or equivalent methods thereto (see Example 62).
    • [A-4]
  • The compound of Z1-L-Ar2 can be prepared by replacing Z3 in the Z3-L-Ar2 (wherein Z3 is a substituent on carbon atom in L ring and represents a halogen atom or a hydrogen atom) with various metal atoms. For example, the reaction can be carried out by reacting Z3-L-Ar2 with diboron reagents (for example, bis(pinacolato)diboron reagent) in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium) or by reacting Z3-L-Ar2 with alkyl lithium reagents (for example, butyl lithium) followed by reacting the resultant compounds with trialkoxy borane reagents (for example, trimethyl borate reagent), respectively in appropriate solvents or under solvent-free condition to prepare boron reagents; by reacting Z3-L-Ar2 with alkyllithium reagents (for example, butyllithium) followed by reacting the resultant compounds with tin chloride reagents (for example, tributyltin chloride) in appropriate solvents or under solvent-free condition to prepare organotin reagents; by reacting Z3-L-Ar2 with zinc dust or diethylzinc in appropriate solvents or under solvent-free condition to prepare zinc reagents; by reacting Z3-L-Ar2 with magnesium powder in appropriate solvents or under solvent-free condition to prepare organomagnesium reagents; by reacting Z3-L-Ar2 with alkyllithium reagents (for example, butyllithium) followed by the resultant compounds with silicon reagents (for example, chlorotrimethylsilane) to prepare organosilicon reagents, respectively in appropriate solvents or under solvent-free condition; by reacting Z3-L-Ar2 with alkyllithium reagents (for example, butyllithium) in appropriate solvents or under solvent-free condition to prepare organolithium reagents. Alternatively, the compound of Z1-L-Ar2 can be prepared, for example, according to the method described in WO 2007/129962 or the like or equivalent methods thereto.
    • [A-5]
  • The compounds of Z1-L-Ar2, Z2-L-Ar2 and Z3-L-Ar2 can be prepared by performing a coupling reaction in Ring L and Ring Ar2 using commercially available starting materials according to the similar methods to those of Process A-1.
    • [A-6]
  • Also, the compounds of Z1-L-Ar2, Z2-L-Ar2 and Z3-L-Ar2 can be prepared by performing a substitution reaction in the case where a binding between Ring L and Ring Ar2 in the Z1-L-Ar2, Z2-L-Ar2 and Z3-L-Ar2 is a N—C bond. For example, the reaction can be achieved, for example, by reacting Ring Ar2 containing a halogen atom as substituent with Ring L containing a NH group in the ring in appropriate solvents or under solvent-free condition in the co-presence of alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example or potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali metal halides (for example, lithium chloride, cesium fluoride) or alkali metal hydroxides (for example, sodium hydroxide) and the others. Also, the reaction may be achieved by performing a cross-coupling reaction on Ring L and Z4—Ar2 (wherein Z4 is a substituent on carbon atom in Ar1 ring and represents a boronic acid, a boronate ester or a halogen atom) in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium or palladium acetate), copper catalysts (for example, copper iodide), zinc reagents or iron chelating reagents and the others optionally with an addition of phosphorus catalysts (for example, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl) or diamine reagents (typically, 1,2-diaminocyclohexane). Also, such coupling reactions may be carried out in the co-presence of alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal phosphates (for example, potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali hydroxides (for example, sodium hydroxide), metal alkoxides (for example, potassium t-butoxide) or the others, in addition to the above-mentioned reagents. For example, the compounds can be prepared, for example, according to the method described in J. Am. Chem. Soc. 1998, 120, 827-828, J. Am. Chem. Soc. 2001, 123, 7727-7729 or J. Org. Chem. 2002, 67, 1699-1702 or equivalent methods thereto.
  • Also, in the case where a binding between Ring L and Ring Ar2 in the Z1-L-Ar2, Z2-L-Ar2 and Z3-L-Ar2 is a C—N bond, the compounds of Z1-L-Ar2, Z2-L-Ar2 and Z3-L-Ar2 can be prepared by performing a substitution reaction on a commercially available Ring Ar2 containing a NH group in the ring and a commercially available Ring L containing a halogen atom as substituent according to a conventional method. This reaction can be achieved according to the similar method to those of Process A-6.
  • Specific examples of solvents to be used for each reaction in Process A should be selected depending on the kind of the starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which may be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process B]
  • The compound of formula (I) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00030
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined as above, X2 represents a halogen atom (for example, iodine atom or bromine atom), and Z5 represents a halogen atom, an amino group or a halogen atom)
    • [Step 1]
  • The compound (III) can be prepared by performing a coupling reaction on the compound (IIb) and Z1-L-Z5 (wherein Z1 is the same as defined above, and Z5 represents a halogen atom or a halogen atom) according to a conventional method. This reaction can be achieved according to the similar methods to those of Process A-1 (see Reference Examples 189 to 191).
  • Also, the compounds (III) can be prepared by converting an X2 group in the compound (IIb) into coupling reactive groups (for example, boron compound group, zinc halide group or magnesium halide group) according to the similar methods to those of Process A-2 followed by performing a coupling reaction on the resultant compounds and Z2-L-Z5 (wherein, Z2 and Z5 are the same as defined above).
    • [Step 2]
  • When Z5 in the compound (III) represents a halogen atom, compound (I) can be prepared by performing a coupling reaction on the compound (III) and Z1—Ar2 (wherein Z1 is the same as defined above) according to a conventional method. This reaction can be achieved according to the similar methods to those of Process A-1 (see Examples 59 to 61).
  • Also, when Z5 in the compound (III) represents a hydrogen atom, the compound (I) can be prepared by performing a halogenation of a L group in the compound (III), followed by performing a coupling reaction of the resultant compounds with Z1—Ar2. For example, this halogenation reaction can be achieved by reacting the compound (III) with halogenating agents (for example, N-iodosuccinimide, N-bromosuccinimide, iodine or bromine), and the coupling reaction can be achieved according to the similar method to those of Process A-1.
  • Also, when Z5 in the compound (III) represents a halogen atom, the compound (I) can be prepared by converting the Z5 group into coupling reactive groups (for example, boron compound group, zinc halide group or magnesium halide group) according to the similar method to those of Process A-2 followed by performing a coupling reaction on the resultant compounds and Ring Ar2 wherein halogen atom is substituted.
  • Also, when Z5 of the compound (III) represents an amino group, the compound (I) can be also prepared by converting the Z5 group into halogen atom (for example, bromine atom or iodine atom) via Sandmeyer reaction according to a conventional method followed by performing a coupling reaction on the resultant compounds and Z1—Ar2 according to the similar method to those of Process A-1. For example, the Sandmeyer reaction can be achieved by reacting the compound (III) with nitrites (typically, sodium nitrite) and copper halides (typically, copper bromide or copper iodide) in appropriate solvents or under solvent-free condition.
  • Also, when L group in the compound (III) contains a NH group in the ring, that is, when a NH group is contained as a L-constituting group, the compound (I) can be prepared by performing a substitution reaction or a coupling reaction on the compound (III) and Z4—Ar2 (wherein Z4 is the same as defined above) according to a conventional method. This reaction can be achieved according to the similar method to those of Process A-6.
  • In the processes, a coupling reaction between Ar2 and L (step 2) can be applied to a coupling reaction in the case of a halogen atom on various substituents for R1 or a halogen atom on Ar1.
  • Specific examples of solvents to be used for each reaction in Process B should be selected depending on the kind of starting materials and the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process C]
  • The compound (I) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00031
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined above, X2 represents a halogen atom, Rx represents —C(═O)H or —CH(ORj)2 and Rj represents an alkyl group having one to six carbon atoms)
    • [Step 1]
  • The compound (IV) can be prepared by performing a coupling reaction on the compound (IIb) and acetylene reagents according to a conventional method. For example, this reaction can be achieved by performing a cross-coupling reaction on the compound (IIb) and various acetylene reagents in appropriate solvents or under solvent-free condition in the co-presence of palladium catalyst (typically, tetrakis(triphenylphosphin)palladium), copper catalyst (typically, copper iodide), alkali carbonates (for example, sodium carbonate, potassium carbonate or cesium carbonate), alkali phosphates (for example, potassium phosphate), organic bases (for example, triethylamine or diisopropylethylamine), alkali halides (for example, lithium chloride or cesium fluoride), alkali hydroxides (for example, sodium hydroxide), metal alkoxides (for example, potassium t-butoxide) and the others (see Reference Example 61, Reference Examples 120-162).
    • [Step 2]
  • When Rx in the compound (IV) represents —C(═O)H or —CH(ORj)2, the compound (I) wherein L represents a pyrazole ring can be prepared by performing a cyclization reaction on the compound (IV) according to a conventional method. For example, this reaction can be achieved by reacting the compound (IV) with Ar2—NH—NH2 in appropriate solvents or under solvent-free condition. The above-mentioned hydrazine compounds may be hydrochloride salts thereof, and the reaction may be optionally carried out in the presence of acids (for example, hydrochloric acid) (see Examples 1-29).
  • Also, this reaction can be achieved by isolating hydrazine compound (as shown in the hydrazine compound of the below-mentioned structure (IV)-1 that produced as a reaction intermediate) followed by performing a cyclization reaction on the resultant compounds. For example, this cyclization reaction can be achieved in the presence of acids (for example, hydrochloric acid or sulfuric acid) or Lewis acids (for example, gold chloride) (see Example 30).
  • Figure US20140179670A1-20140626-C00032
  • Also, the compound (I) wherein L represents a pyrazole ring can be prepared by performing a cyclization reaction on the compound (IV) and hydrazines according to a conventional method followed by performing a coupling reaction on the resultant compounds and Z4—Ar2 (wherein Z4 is the same as defined above) according to the similar method to those of Process [A-6]. The hydrazines to be used in this reaction may be hydrates or hydrochloride salts thereof and the reaction may be optionally carried out in the presence of acids (for example, hydrochloric acid) or transition metal catalysts (for example, gold(III) chloride).
  • When Ar2 contains an amino group as a substituent, the compound of Ar2—NH—NH2 can be prepared by converting the amino group into the hydrazine group according to a conventional method. For example, this reaction can be achieved by reacting the compounds with sodium nitrite or nitrite esters in the presence of acids (for example, hydrochloric acid) in appropriate solvents or under solvent-free condition followed by reacting the resultant compounds with reducing agents (for example, tin(II chloride) (see Reference Example 198).
  • Specific examples of solvents to be used for each step in Process C should be selected depending on the kind of starting materials and the kind of reagents used and includes, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process D]
  • The compound (I) wherein R1 represents an C1-10 alkyl group substituted with C(═O)OH or S(═O)mOH, an C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ib)], the compounds (I) wherein R1 represents an C1-10 alkyl group substituted with C(═O)NRcRd, S(═O)mNRcRd or C(═O)ORb, an C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ic)] can be prepared according to the below-mentioned Processes.
  • Figure US20140179670A1-20140626-C00033
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R1a represents an C1-10 alkyl group substituted with C(═O)ORb or S(═O)mORb, an C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1b represents a C1-10 alkyl group substituted with —C(═O)OH or —S(═O)mOH, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1c represents a C1-10 alkyl group substituted with C(═O)NRcRd, S(═O)mNRcRd or C(═O)ORb, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, and Rb, Rc, Rd and m are the same as defined above)
    • [Step 1]
  • The compound (Ib) can be prepared by performing a hydrolysis reaction on the compound (Ia) according to a conventional method. For example, this reaction can be achieved by performing a hydrolysis reaction in appropriate solvents or under solvent-free condition, under alkaline condition (for example, sodium hydroxide) or acidic condition (for example, hydrochloric acid) (see Examples 73 and 74).
  • Also, when Rb in the compound (Ia) represents a benzyl group optionally substituted with nitro or methoxy, the compound (Ib) can be prepared by performing a reduction reaction on the compound (Ia) according to a conventional method. For example, this reaction can be achieved by performing the reaction with catalytic reduction reagents (for example, palladium on carbon or palladium hydroxide) in charged states of hydrogen gas or in the presence of ammonium formate in appropriate solvents or under solvent-free condition, by performing the reaction in the presence of acids (for example, trifluoroacetic acid), or by performing the reaction in the presence of oxidizing agent (for example, 2,3-dichloro-5,6-dicyano-para-benzoquinone) (see Example 72).
    • [Step 2]
  • The compound (Ic) can be prepared by performing an amidation reaction or an esterification reaction on the compound (Ib) according to a conventional method. For example, this reaction can be achieved by converting the compound (Ib) into reactive derivatives thereof (for example, active esters, anhydrides or acid halides) in appropriate solvents or under solvent-free condition followed by reacting the resultant compounds with various amines or various alcohols. Specific examples of active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester, 2-pyridylthiol ester, N-methylimidazole ester and the others. The anhydrides may be used as symmetrical anhydrides or mixed anhydrides. Specific examples of mixed anhydrides include mixed anhydrides of ethyl chlorocarbonate and isovaleric acid, and the others.
  • Also, the compound (Ic) can be prepared by reacting the compound (Ib) with various amines and various alcohols in the presence of a condensing agent according to a conventional method. Specific examples of the condensing agent include N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.monohydrochloride, N,N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate and the others. These condensing agents may be used alone or in combination with peptide synthesis reagents (for example, N-hydroxysuccinimide or N-hydroxybenzotriazole) (see Examples 75-82).
  • The hydrolysis reaction of ester group, or the amidation reaction or esterification reaction shown in the above-mentioned processes may be applied to the case where the ester group on Ar1, L, Ar2 and the others is converted into a carboxyl group, an amide group or an ester group (see Examples 103-106, Examples 142-145).
  • Specific examples of solvents to be used for each step in Process D should be selected depending on the kind of starting materials and the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process E]
  • The compound (I) wherein R1 represents a C1-10 alkyl group substituted with NHRa, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ie)], the compound (I) wherein R1 represents a C1-10 alkyl group substituted with NRaC(═O)Rb, NRaC(═O)NRcRd or NRaS(═O)mRb, a C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (If)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00034
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R1d represents a C1-10 alkyl group substituted with NRaC(═O)ORb, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1e represents a C1-10 alkyl group substituted with NHRa, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1f represents a C1-10 alkyl group substituted with NRaC(═O)Rb, NRaC(═O)NRcRd or NRaS(═O)mRb, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, and Ra, Rb, Rc and Rd are the same as defined above)
    • [Step 1]
  • The compound (Ie) can be prepared by performing a deprotection of a carbamate group in the compound (Id) via a hydrolysis reaction or a reduction reaction. For example, this reaction can be achieved according to the similar method to those of [Step 1] in Process D (see Example 85).
    • [Step 2]
  • The compound (If) can be prepared by performing an amidation reaction on the compound (Ie) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ie) with active ester, anhydrides or acid halides each being derivatized from carboxylic acid derivatives and sulfonic acid derivatives in appropriate solvents or under solvent-free condition. Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxypiperidine ester, 2-pyridylthiol ester, N-methylimidazole ester and the others. The anhydrides may be used as symmetrical anhydrides or mixed anhydrides. Specific examples of mixed anhydrides include a mixed anhydride of ethyl chlorocarbonate and isovaleric acid, and the others (see Example 86, Example 113).
  • Also, the compound (If) can be prepared by reacting the compound (Ie) with various carboxylic acids and various sulfonic acids in the presence of a condensing agent according to a conventional method. Specific examples of the condensing agent include N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride, N,N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate, and the others. These condensing agents may be used alone or in combination with peptide synthesis reagents (for example, N-hydroxysuccinimide or N-hydroxybenzotriazole).
  • Also, the compound (If) can be prepared by performing an urea formation on the compound (Ie) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ie) with various substituted isocyanate compounds and the others in appropriate solvents or under solvent-free condition. Also, the compound (If) can be prepared by converting the compound (Ie) into reactive derivatives thereof (for example, active carbamates) followed by reacting the resultant compounds with various amines according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ie) with phenyl chloroformate, carbodiimidazole or the others followed by reacting the resultant compounds with various amines in appropriate solvents or under solvent-free condition. Such urea formation reactions may be optionally carried out in metal hydride reagents (for example, sodium hydride or potassium hydride), inorganic bases (for example, potassium carbonate or sodium hydrogen carbonate) or organic bases (for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine).
  • The deprotection reaction of carbamate, an amidation reaction or an urea formation reaction as shown in the above-mentioned processes can be applied to the case of a deprotection reaction of a carbamate group, an amidation reaction or an urea formation reaction on Ar1, L, Ar2 or R1 other than the above-mentioned ones (see Example 112).
  • Specific examples of solvents to be used for Process E should be selected depending on the kind of starting materials or the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, or alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Step F]
  • The compound of formula (I) wherein R1 represents a C1-10 alkyl group substituted with hydroxy, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ih)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00035
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R1g represents a C1-10 alkyl group substituted with CO2Rb, C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1h represents a C1-10 alkyl group substituted with hydroxy, a C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, and Rb is the same as defined above)
  • The compound (Ih) can be prepared by performing a reduction reaction on the compound (Ig) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ig) with reducing agents (for example, borane tetrahydrofuran complex or lithium aluminium hydride) in appropriate solvents, or alternatively when Rb represents a hydrogen atom, can be achieved by reacting the compound (Ig) with anhydrides or acid halides so as to be derivatized to a mixed anhydrides, followed by treating the resultant mixed anhydrides with reducing agents (for example, sodium borohydride) (see Examples 83, 84 and 122).
  • The reduction reaction on ester group or carboxyl group as shown in the above-mentioned processes may be applied to the case of a reduction on the ester group or the carboxyl group on Ar1, L or Ar2 (see Example 138).
  • Specific examples of solvents to be used in Process F should be selected depending on the kind of starting materials or the kind of reagents used, and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Step G]
  • The compound of formula (I) wherein R1 represents a C1-10 alkyl group substituted with hydroxy, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ih)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00036
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R1i represents a C1-10 alkyl group substituted with OCORa, a C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1h represents a C1-10 alkyl group substituted with hydroxy, a C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, and Ra is the same as defined above)
  • The compound (Ih) can be prepared by performing a reduction reaction on the compound (Ii) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ii) with reducing agents (for example, diisobutylaluminium hydride or lithium aluminium hydride) in appropriate solvents.
  • Also, the compound (Ih) can be prepared by performing a hydrolysis reaction on the compound (Ii) according to a conventional method. For example, this reaction can be achieved by performing a hydrolysis reaction on the compound (Ii) under basic condition with bases (for example, potassium carbonate or sodium hydroxide) or under acidic condition with acids (for example, hydrochloric acid) (see Examples 109-110).
  • Specific examples of solvents to be used in Process G should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process H]
  • The compound of formula (I) wherein R1 represents a hydrogen atom [the below-mentioned compound of formula (Ik)] and the compound of formula (I) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00037
  • (wherein, Ar1, L, Ar2, R1 and R2 are the same as defined above, and R1j represents a benzyl group optionally substituted with nitro or methoxy)
    • [Step 1]
  • The compound (Ik) can be prepared by performing a reduction reaction on the compound (Ij) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ij) with catalytic reduction reagents (for example, palladium on carbon or palladium hydroxide) in charged states of hydrogen gas or in the presence of ammonium formate, by performing a reaction in the presence of acids (for example, trifluoroacetic acid), or by performing a reaction in the presence of oxidizing agents (for example, 2,3-dichloro-5,6-dicyanopara-benzoquinone).
    • [Step 2]
  • The compound (I) can be prepared by performing an alkylation reaction on the compound (Ik) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ik) with various alkylhalides reagents in the presence of hydrogenated metal reagents (for example, sodium hydride), alkali metal carbonates reagents (for example, potassium carbonate), alkali metal phosphates reagents (for example, potassium phosphate), organic bases reagents (for example, triethylamine), alkali metal halides reagents (for example, lithium chloride), alkali metal hydroxides (for example, sodium hydroxide), metal alkoxides (for example, potassium t-butoxide) or the others in appropriate solvents or under solvent-free condition.
  • Also, the compound (I) can be prepared by performing Mitsunobu reaction on the compound (Ik) and the corresponding alcohols according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ik) with the corresponding alcohols in the presence of a condensing agent (for example, a combination of triphenyl phosphine and diethyl azodicarboxylate) in appropriate solvents or under solvent-free condition.
  • Specific examples of solvents to be used in Process H should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process I]
  • The compound of formula (I) wherein Bb as a part of a substituent of L represents —NRaC(═O)Rb [the below-mentioned compound of formula (Im)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00038
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined above, Ba represents —NRa—, Bb represents —NRaC(═O)—, and Ra and Rb are the same as defined above)
  • The compound (Im) can be prepared by performing an amidation reaction on the compound (Ii) according to the similar method to those of [Step 2] in Process E.
  • Specific examples of solvents to be used in Process I should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process J]
  • The compound of formula (I) wherein BC as a part of a substituent of L represents —O— or —NRc— [the below-mentioned compound of formula (Io)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00039
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined above, Bc represents —O— or —NRc—, and Rd is the same as defined above)
  • The compound (Io) can be prepared by using the compound (In) according to the similar method to those of [Step 2] in Process H, or can be prepared by performing an alkylation reaction via a reductive amination on the compound (In) (see Example 141).
  • Specific examples of solvents to be used in Process J should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process K]
  • The compound of formula (I) wherein Be as a part of a substituent of L represents a halogen atom [the below-mentioned compound of formula (Iq)], the compound of formula (I) wherein Bf as a part of a substituent of L represents —C(═O)— [the below-mentioned compounds of formula (Ir) and formula (Is)], the compound of formula (I) wherein Bg as a part of a substituent of L represents —C(═O)NRc— [the below-mentioned compound of formula (It)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00040
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined above, Bd represents a hydrogen atom, Be represents a halogen atom, Bf represents —C(═O)—, Bg represents —C(═O)NRc—, and Ra and Rd are the same as defined above)
    • [Step 1]
  • The compound (Ig) can be prepared by performing a halogenation reaction on the compound (Ip) according to the similar method to those of [Step 2] in the Process B (see Examples 93 to 101). Also, the compound (Iq) wherein Be represents a fluorine atom can be prepared by performing a fluorination reaction on the compound (Ip) according to a conventional method. For example, this reaction can be achieved by reacting the compound (1) with fluorination agents (for example, Selectfluor (trade mark)) in appropriate solvents or under solvent-free condition (see Example 358).
    • [Step 2]
  • The compound (Ir) can be prepared by performing a carbon monoxide insertion reaction on the compound (Iq) in the presence of alcohols (see Example 134).
    • [Step 3]
  • The compound (Is) can be prepared by performing a hydrolysis reaction or a reduction reaction on the compound (Ir) according to the similar method to those of [Step 1] of Process D.
    • [Step 4]
  • The compound (Is) can be prepared by performing a carbon monoxide insertion reaction on the compound (Iq) in the presence of water according to the similar method to those of [Step 2] of Process K (see Examples 132 to 133).
    • [Step 5]
  • The compound (It) can be prepared by performing an amidation reaction on the compound (Is) according to the similar method to those of [Step 2] in Process D (see Examples 142 to 145).
  • Specific examples of solvents to be used for each step in the Process K should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 1200° C., and the reaction may be optionally carried out under pressurized condition.
    • [Step L]
  • The compound of formula (I) wherein Bh as a part of a substituent of L represents an optionally substituted alkyl group, an optionally substituted alkene group or a cyano group [the below-mentioned compound of formula (Iu)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00041
  • (wherein, R1, Ar1, L, Ar2 and R2 are the same as defined above, Be represents a halogen atom, Bh represents an optionally substituted alkyl group, an optionally substituted alkene group or a cyano group)
    • [Step 1]
  • The compound (Iu) can be prepared by performing a coupling reaction on the compound (Iq). This reaction can be achieved according to the similar method to those of Process A-1. Also, a cyanation reaction can be achieved by using cyano coupling agents (for example, zinc cyanide or copper cyanide) (see Examples 126 to 131 and 363).
  • Specific examples of solvents to be used for each step in Process L should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process M]
  • The compound of formula (I) wherein R1 represents a C1-10 alkyl group substituted with alkoxy, alkylthio, alkylamino or dialkylamino, an C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Iw)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00042
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R19 represents a C1-10 alkyl group substituted with hydroxy, thio, amino, monoalkylamino, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1k represents a C1-10 alkyl group substituted with alkoxy, alkylthio, alkylamino or dialkylamino, a C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S)
  • The compound (Iw) can be prepared by performing an alkylation reaction on the compound (Iv) according to the similar method to those of [Step 2] in Process H.
  • The method for an alkylation reaction shown in the above-mentioned processes can be also applied to the case where OH, SH, NH2 or NHRa on Ar1, L or Ar2 is alkylated.
  • Specific examples of solvents to be used in the Process M should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process N]
  • The compound of formula (I) wherein R1 represents a C1-10 alkyl group substituted with aldehyde, a C2-6 alkene group, or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Iy)] and the compound of formula (I) wherein R1 represents a C1-10 alkyl group substituted with monoalkylamino group or dialkylamino group, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Iz)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00043
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R11 represents a C1-10 alkyl group substituted with acetal (CH(ORj)2), a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1m represents a C1-10 alkyl group substituted with aldehyde, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, R1n represents a C1-10 alkyl group substituted with monoalkylamino or dialkylamino, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, and Rj is the same as defined above)
    • [Step 1]
  • The compound (Iy) can be prepared by performing a deprotection reaction on acetal group in the compound (Ix) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ix) with acids (for example, p-toluenesulfonic acid, trifluoroacetic acid or hydrochloric acid) in appropriate solvents or under solvent-free condition (see Example 68).
    • [Step 2]
  • The compound (Iz) can be prepared by performing a reductive amination reaction on the compound (Iy) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Iy) with monoalkylamine or dialkylamine in the co-presence of hydride reagents (for example, sodium borohydride, triacetoxysodium borohydride or sodium cyanoborohydride) and acids (for example, acetic acid or hydrochloric acid) in appropriate solvents or under solvent-free condition (see Examples 69 to 70).
  • The deprotection of acetal group as shown in the Step 1 of the above-mentioned processes may be applied to the case of a conversion reaction of acetal group on Ar1, L and Ar2 into aldehyde group.
  • Specific examples of solvents to be used in Process N should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Step O]
  • The compound of formula (I) wherein R1 represents a C1-10 alkyl group substituted with aldehyde, oxo, carboxyl, sulfonyl or sulfoxide, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S [the below-mentioned compound of formula (Ib′)] can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00044
  • (wherein, Ar1, L, Ar2 and R2 are the same as defined above, R1o represents a C1-10 alkyl group substituted with hydroxy, aldehyde, thiol, alkylthio or sulfoxide, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, and R1p represents a C1-10 alkyl group substituted with aldehyde, oxo, carboxyl, sulfoxide or sulfonyl, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S)
  • When R1o in the compound (Ia′) represents a C1-10 alkyl group substituted with hydroxy or aldehyde, a C2-6 alkene group or a three- to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, the compound (Ia′) is oxidized according to a conventional method to produce the compound (Ib′) wherein R1p represents a C1-10 alkyl group substituted with oxo or carboxyl, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S. For example, this reaction can be achieved by reacting the compound (Ia′) with oxidizing agents (for example, Dess-Martin reagent, potassium dichromate, sodium hypochlorite, Jones reagent or pyridinium dichromate).
  • Also, when R1o in the compound (Ia′) represents a C1-10 alkyl group substituted with thiol or sulfoxide, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S, the compound (Ia′) can be oxidized according to a conventional method to produce the compound of the formula (Ib′) wherein R1p represents a C1-10 alkyl group substituted with sulfoxide or sulfonyl, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S. For example, this reaction can be achieved by reacting the compound (Ia′) with peroxidizing reagents (for example, meta-chloroperbenzoic acid or hydrogen peroxide) in appropriate solvents.
  • The oxidation reaction as shown in the above-mentioned processes may be applied to the case of an oxidation reaction of methyl alcohol, methylthiol, aldehyde or sulfoxide as a substituent of Ar1, L and Ar2 so as to convert it into aldehyde, carboxylic acid, sulfoxide or sulfonyl respectively.
  • Specific examples of solvents to be used for each reaction in Process O should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process P]
  • The compound (I) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00045
  • (wherein, Ar1, L, Ar2, R1 and R2 are the same as defined above, and X2 represents a halogen atom (for example, iodine atom or bromine atom).)
    • [Step 1]
  • The compound (Id′) can be prepared by performing a halogenation reaction on the compound (Ic′) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Ic′) with halogenating agents (for example, N-iodosuccinimide, N-bromosuccinimide, a combination of potassium iodide and cerium ammonium nitrate, iodine or bromine) in appropriate solvents or under solvent-free condition.
    • [Step 2]
  • When R2 in compound (I) represents an alkyl group, the compound (I) can be prepared by performing a coupling reaction on the compound (Id′) and Z1—R2 (wherein Z1 is the same as defined above) according to a conventional method. This reaction can be achieved according to the similar method to those of Process A-1.
  • Also, when R2 in the compound (I) represents an amino group, the compound (I) can be prepared by performing an amination reaction on the compound (Id′) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Id′) with aminating agents (for example, ammonia, ammonium salt, alkylamine reagents or dialkylamine reagents) in appropriate solvents or under solvent-free condition. Also, this reaction can be achieved by performing an amination reaction on the compound (Id′) and various amine reagents in the presence of palladium catalysts (for example, tetrakis(triphenylphosphin)palladium), copper reagents (for example, copper iodide), zinc reagents or iron chelating reagents, optionally with an addition of phosphorus catalyst (typically, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl).
  • Also, when R2 in the compound (I) represents a cyano group, the compound (I) can be prepared by performing a cyanation reaction on the compound (Id) according to a conventional method. For example, this reaction can be achieved by reacting the compound (Id′) with cyanating agents (for example, potassium cyanide, sodium cyanide or copper cyanide). Also, this reaction can be also achieved in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium), copper catalysts (typically, copper iodide), zinc reagents or iron chelating reagents, optionally with an addition of phosphorus catalyst (for example, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl).
  • Specific examples of solvents to be used in Process P should be selected depending on the kind of starting materials or the kind of reagents used and include, for example, dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 150° C., preferably within a range of 0° C. to 120° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process Q]
  • Next, the starting materials (IIa) and (IIb) to be used in the above-mentioned Processes A to C are known compounds or are prepared, for example, according to the method shown in the below-mentioned reaction scheme. Herein, the compound (IIa) represents the below-mentioned compound (VII) wherein X3 represents a halogen atom or the below-mentioned compound (VIII) wherein X3 represents an amino group, and the compound (IIb) represents the below-mentioned compound (VII) wherein X3 represents a halogen atom.
  • Figure US20140179670A1-20140626-C00046
  • (wherein, Ar1, R1 and R2 are the same as defined above, and X3 represents a chlorine atom, a bromine atom, an iodine atom or a nitro group)
  • The compound (V) is a well-known compound or can be prepared according to equivalent processes to those for known compounds. For example, said compound can be prepared according to the method described in Journal of Medicinal Chemistry, 2004, 47(7), 1617-1630 and the others, or equivalent methods thereto.
    • [Step 1]
  • The compound (VI) wherein R2 represents a methyl group is a known compound or can be prepared by using the compound (V) according to equivalents processes to known processes. For example, said compound can be prepared according to the methods described in Heterocycles, 1993, 36(2), 307-314, J. Med. Chem. 2008, 51, 7478 and the others, or equivalent methods thereto.
  • Also, the compound (VI) wherein R2 represents an amino group is a known compound or can be prepared by using the compound (V) according to equivalent processes to known processes. For example, said compound can be prepared according to the method described in Chemical & Pharmaceutical Bulletin 1989, 37(8), 2008-2011 and the others or equivalent methods thereto.
  • Also, the compound (VI) wherein R2 represents a hydrogen atom is a known compound or can be prepared by using the compound (V) according to equivalent processes to known processes. For example, said compound can be prepared according to the methods described in Synthesis 1986, (12), 1041-1044 or equivalent processes thereto.
  • The compound (VI) and the compound (VII) wherein in both formulae, R2 represents —N═CHN(CH3)2 can be prepared by reacting the compounds with N,N-dimethylformamide dimethyl acetal in appropriate solvents or under solvent-free condition according to a conventional method.
  • Also, the compound (VI) and the compound (VII) wherein in both formulae, R2 represents —N═CHN(CH3)2 can be performed a deprotection reaction under acidic condition (for example, hydrochloric acid or trifluoroacetic acid) or under alkali condition (for example, aqueous sodium hydroxide solution) so as to convert into the compound (VI) and the compound (VII) wherein in both formulae, R2 represents NH2 (see Reference Example 52, and Examples 57 and 58).
    • [Step 2]
  • The compound (VII) can be prepared by performing a halogenation reaction or a nitration reaction on the compound (VI) according to a conventional method. For example, the halogenation reaction can be achieved by reacting the compound (VI) with halogenating agents (for example, N-iodosuccinimide, N-bromosuccinimide, a combination of potassium iodide and ammonium cerium nitrate, iodine and bromine) in appropriate solvents or under solvent-free condition. The nitration reaction can be achieved by reacting the compound (VI) with nitrating agents (for example, fuming nitric acid) in appropriate solvents or under solvent-free condition (see Reference Examples 60, 62-94 and 192).
    • [Step 3]
  • When X3 in the compound (VII) represents a nitro group, the compound (VIII) can be prepared by performing a reduction reaction on the compound (VII) according to a conventional method. For example, this reaction can be achieved by reacting the compound (VII) with metal reagents (for example, palladium on carbon, platinum oxide, Raney nickel or reduced iron) in charged states of hydrogen gas or in the co-presence of ammonium chloride in appropriate solvents or under solvent-free condition (see Reference Examples 193 and 197).
  • Also, when X3 in the compound (VII) represents a halogen atom, the compound (VIII) can be prepared by performing an amination reaction on the compound (VII) according to a conventional method. For example, this reaction can be achieved by reacting the compound (VII) with amine reagents (for example, ammonia or ammonium salt) in appropriate solvents or under solvent-free condition.
  • Specific examples of solvents to be used for each reaction in Process P should be selected depending on the kind of starting materials and include, for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 200° C., preferably within a range of 0° C. to 150° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process R]
  • Also, in the above-mentioned Process Q, the compound (VI) wherein R2 represents a hydrogen atom can be also prepared according to the below-mentioned reaction scheme. Herein, the above-mentioned compound (VI) represents the compound (XIII) and the compound (XIV).
  • Figure US20140179670A1-20140626-C00047
  • (wherein, Ar1 and R1 are the same as defined above, and R111 and R222 represent independently of each other an alkyl group having one to six carbon atoms)
  • The compound (IX) is a known compound or can be prepared according to equivalent processes to a process for known compound. For example, said compound can be prepared, for example, according to the method described in Chemical & Pharmaceutical Bulletin, 1972, 20(7), 1380-1388 or equivalent methods thereto.
    • [Step 1]
  • The compound (XI) is a known compound or can be prepared by using the compound (IX) and the compound (X) according to equivalent processes to a known process. For example, said compound can be prepared, for example, according to the method described in Chemical & Pharmaceutical Bulletin, 1972, 20(7), 1380-1388 or equivalent method thereto (see Reference Examples 111 and 115).
    • [Step 2]
  • The compound (XII) is a known compound or can be prepared by performing a cyclization reaction on the compound (XI) according to equivalent processes to a known process. For example, said compound can be prepared, for example, according to the method described in Bioorganic & Medicinal Chemistry, 2006, 14(7), 3399-3404 and the others or equivalent methods thereto (see Reference Examples 112 and 116).
    • [Step 3]
  • The compound (XIII) is a known compound or can be prepared by converting a cyano group in the compound (XII) into a hydrogen atom according to equivalent processes to known process. For example, said compound can be prepared, for example, according to a method described in Chemical & Pharmaceutical Bulletin, 1972, 20(7), 1389-1396 or equivalent methods thereto (see Reference Examples 113 and 117).
    • [Step 4]
  • The compound (XIV) can be prepared, for example, in the presence of bases, by performing a reaction of the compound (XIII) with electrophilic reagents (for example, halogenated alkyl or carbamates), or by performing Mitsunobu reaction on the compound (XIII) and alcohols. Examples of the bases include metal hydrides (for example, sodium hydride), alkali or alkaline-earth carbonates (for example, potassium carbonate) or tertiary amine (for example, triethylamine) (see Reference Examples 100 and 101).
  • Specific examples of solvents to be used for each reaction in Process R should be selected depending on the kind of starting materials and include, for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which may be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents and the others, and includes usually within a range of −40° C. to 200° C., preferably within a range of 0° C. to 150° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process S]
  • Also, in the above-mentioned Process R, the compound (XIII) can be prepared according to the below-mentioned reaction scheme.
  • Figure US20140179670A1-20140626-C00048
  • (wherein, Ar1 is the same as defined above)
    • [Step 1]
  • The compound (XV) is a known compound or can be prepared by reacting the compound (X) with acrylic acid according to equivalent processes to the known process. For example, said compound can be prepared, for example, according to the method described in WO 2009/39127 A1 and the others or equivalent methods thereto (see Reference Example 95).
    • [Step 2]
  • The compound (XVI) is a known compound or can be prepared by reacting the compound (XV) with urea according to equivalent processes to known process. For example, said compound can be prepared, for example, according to the method described in WO 2009/39127 A1 and the others or equivalent methods thereto (see Reference Example 96).
    • [Step 3]
  • The compound (XIII) can be prepared by reacting the compound (XVI) with bromine followed by the resultant compound with Lewis acids (for example, lithium chloride) or bases according to a conventional process. For example, said compound can be prepared, for example, according to the method described in Journal of Organic Chemistry, 2002, 67(5), 1480-1489, Journal of the American Chemical Society, 1956, 78, 1612-1614 or the others or equivalent methods thereto (see Reference Example 98).
  • Specific examples of solvents to be used in Process S should be selected depending on the kind of starting materials and the others and include, for example, water, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 200° C., preferably within a range of 0° C. to 100° C., and the reaction may be optionally carried out under pressurized condition.
    • [Process T]
  • Also, in the above-mentioned Process S, the compound (XIII) can be also prepared according to the below-mentioned reaction scheme.
  • Figure US20140179670A1-20140626-C00049
  • (wherein, Ar1 is the same as defined above)
  • The compound (XIII) can be prepared by performing an arylation reaction on the compound (XVII) according to a conventional method. For example, said compound can be prepared, for example, according to the method described in Helvetica Chimica Acta, 2008, 91(6), 1008-1014 or equivalent thereto (see Reference Examples 99).
  • Specific examples of solvents to be used in Process T should be selected depending on the kind of starting materials and include, for example, water, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 200° C., preferably within a range of 0° C. to 100° C.
    • [Process U]
  • Also, in the compounds (I), (IIa), (IIb), (III), (IV), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Ib′), (Ic′), (Id′), (VI), (VII) or (VIII) in the above-mentioned processes, when R1 represents a hydrogen atom, that is, a formula (XVIII), R1 other than a hydrogen atom can be introduced according to the below-mentioned reaction scheme so as to convert it into the compound (XIX).
  • Figure US20140179670A1-20140626-C00050
  • (wherein, Ar1, R1 and R2 are the same as defined above, L1 represents a hydrogen atom, X1, X2, X3, Ar2-L-, Z5-L- or a substituent represented by the following formulae:
  • Figure US20140179670A1-20140626-C00051
  • X1, X2, X3, L, Ar2, Z5, Rx, Rb, Rd, Ba, Bb, Bc, Bd, Be, Bf and Bg are the same as defined above)
  • The compound (XIX) can be prepared by performing a reaction of the compound (XVIII) with alkyl compounds having a leaving group (for example, halogenated alkyls) in the presence of bases according to a conventional method, or by performing a Mitsunobu reaction on the compound (XVIII) and alcohols. The bases may use as metal hydrides (for example, sodium hydride), metal alkoxides (for example, potassium tert-butoxide), alkali or alkaline-earth carbonates (for example, potassium carbonate) or tertiary amines (for example, triethylamine). Also, as for the condition for Mitsunobu reaction, azodicarboxylic acid diisopropyl ester and the like as well as triphenyl phosphine and the like can be used in combination (see Reference Examples 100, 101, 104, 105, 119, Examples 88-92).
  • Specific examples of solvents to be used in Process U should be selected depending on the kind of starting materials and include, for example, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, acetic acid, and alcohols (for example, methanol, ethanol or isopropanol) and the others, which can be used alone or as a mixed solvent thereof. The reaction temperature may be varied depending on the kind of starting materials used and the kind of reagents used and the others, and includes usually within a range of −40° C. to 200° C., preferably within a range of 0° C. to 100° C.
    • [Process V]
  • The compounds of formula (2), formula (3), formula (4), formula (6), formula (7) and formula (8) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00052
  • (wherein, Ar1, R1, R2, Ar2, Rc2, Rd2 and Rg3 are the same as defined above, and X2 represents a halogen atom (for example, iodine atom or bromine atom))
    • [Step 1]
  • The compound (2) can be prepared by performing a sulfonation reaction on the compound (1) according to a conventional method. For example, this reaction can be achieved by reacting the compound (1) with sulfuric acid or chlorosulfonic acid in appropriate solvents or under solvent-free condition (see Example 191).
    • [Step 2]
  • The compound (3) can be prepared by performing an acid chlorination reaction on the compound (2) according to a conventional method. For example, this reaction can be achieved by reacting the compound (2) with phosphorus oxychloride, oxalyl chloride, phosphorus pentachloride or the others in appropriate solvents or under solvent-free condition. Such acid chlorination reaction may be optionally carried out in the presence of organic bases (for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine) (see Example 204).
    • [Step 3]
  • The compound (4) can be prepared by performing a sulfonamidation reaction on the compound (3) according to a conventional method. For example, this reaction can be achieved by reacting the compound (3) with amine reagents in appropriate solvents or under solvent-free condition. Such solfonamidation reaction may be optionally carried out in the presence of hydrogenated metal reagents (for example, sodium hydride or potassium hydride), inorganic bases (for example, potassium carbonate or sodium hydrogen carbonate) or organic bases (for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine).
  • Also, when either of Rc2 or Rd2 in the compound (4) represents an alkyl group containing asymmetric carbon (for example, (R) or (S)-1-phenethyl group or (R) or (S)-2-phenylethanol group), the compound (4) may form diastereoisomer compounds, and the resultant atropisomers can be thus resolved (see Examples 205, 212, 217-259).
    • [Step 4]
  • The compound (7) can be prepared by converting a chloro group in the compound (3) into a methyl group according to a conventional method. For example, this reaction can be achieved by reacting the compound (3) with methyl iodide, sodium sulfite or sodium hydrogen carbonate in appropriate solvents or under solvent-free condition. For example, said compound can be prepared, for example according to the method described in J. Med. Chem. 2003, 46(23), 4955 and the others, or equivalent methods thereto (see Example 265).
    • [Step 5]
  • The compound (6) can be prepared by performing a coupling reaction on the compound (5) according to a conventional method. For example, this reaction can be achieved by reacting the compound (5) with sulfur reagents in appropriate solvents or under solvent-free condition. Also, the reaction can be achieved by performing an amination reaction on the compound (5) and various sulfur reagents in the presence of palladium catalysts (typically, tetrakis(triphenylphosphin)palladium) or copper catalysts (for example, copper iodide), zinc reagents or iron chelating reagents optionally with an addition of phosphorus catalysts (for example, 2,2′-bis(diphenylphosphino)-1,1-binaphthalene or 2-(di-t-butyl)phosphinobiphenyl) (see Example 269).
    • [Step 6]
  • The compound (2) and the compound (7) can be prepared by performing an oxidation reaction on the corresponding compound (6) according to a conventional method. For example, this reaction can be achieved by reacting the compound (6) with peroxidizing agents (for example, meta-chloroperbenzoic acid or hydrogen peroxide) in appropriate solvents or under solvent-free condition (see Example 270).
    • [Step 7]
  • In order to obtain sulfonamide derivative as atropisomer, the compound (4) wherein either of Rc2 or Rd2 represents a benzyl derivative group (for example, (R) or (S)-1-phenethyl group or (R) or (S)-2-phenylethanol group) is performed a diastereomer resolution followed by performing a deprotection reaction of the benzyl group according to a conventional method so as to produce compound (8) as one of the atropisomer. For example, the deprotection reaction can be achieved according to the similar method to those of Step 1 in Process H (see Examples 262 and 263).
    • [Step 8]
  • The compound (7) can be prepared by performing a coupling reaction on the compound (5) according to a conventional method. For example, this reaction can be achieved by using alkyl sulphinates (for example, sodium methane sulphinate) in appropriate solvents or under solvent-free condition according to the similar method to those of [Step 5] (see Example 275).
    • [Process W]
  • The compound (II) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00053
  • (wherein, Ar1, R2, L and Ar2 are the same as defined above, R11 represents a C1-6 alkyl group substituted with hydroxy or a three to six-membered aliphatic ring group, R12 represents a C1-6 alkyl group substituted with iodine or tosylate, or a three to six-membered aliphatic ring group, and R13 represents a C1-6 alkyl group substituted with thiol, alkylthio or amino or a three to six-membered aliphatic ring group)
    • [Step 1]
  • The compound (10) can be prepared by performing a halogenation reaction or a tosylation reaction on the compound (9) according to a conventional method. For example, such halogenation reaction can be achieved by reacting the compound (9) with halogenating agents (for example, iodine or bromine) in appropriate solvents or under solvent-free condition. Such halogenation reaction may be optionally carried out in the presence of imidazole, triphenyl phosphine or the others. Also, such tosylation reaction can be achieved by reacting the compound (9) with tosyl chloride in appropriate solvents or under solvent-free condition. The tosylation reaction may be carried out in the presence of organic bases (for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine) (see Example 374).
    • [Step 2]
  • The compound (11) can be prepared by performing a nucleophilic reaction on the compound (10) according to a conventional method. For example, among the nucleophilic reactions, the thiolation reaction can be achieved by reacting the compound (10) with sodium hydrosulfide in appropriate solvents or under solvent-free condition. Alternatively, the reaction can be also achieved by reacting the compound with thiorea followed by reacting with sodium disulfite. Also, such thioalkylation reaction or amination reaction can be achieved by reacting the compound (10) with alkylthio reagents or amino reagents in appropriate solvents or under solvent-free condition. Such nucleophilic reaction may be optionally carried out in the presence of hydrogenated metal reagents (for example, sodium hydride or potassium hydride), inorganic bases (for example, potassium carbonate or sodium hydrogen carbonate) or organic bases (for example, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine) (see Example 374).
  • The Process W can be also applied to the case of Za in the below-mentioned compound of formula (12) (wherein, Ar1, R2, L or Ar2 are the same as defined above, and Za represents a C1-6 alkyl group substituted with hydroxy or a three to six-membered aliphatic ring group).
  • Figure US20140179670A1-20140626-C00054
    • [Process X]
  • The compound (16) can be prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00055
  • (wherein, Ar1, R1, R2 and Ar2 are the same as defined above, and Z2 represents an optionally substituted C1-6 alkyl group, a three to six-membered aliphatic ring group, —C(═O)NRcRd or —C(═O)ORb2)
    • [Step 1]
  • The compound (14) can be prepared by performing an amidation reaction on the compound (13) according to a conventional method. The reaction can be achieved according to the similar method to those of Step 2 in Process D (See Reference Examples 240 and 243).
    • [Step 2]
  • The compound (15) can be prepared by performing a thioamidation reaction on the compound (14) according to a conventional method. For example, the reaction can be achieved by reacting the compound (14) with sulfurizing agents (for example, Lawesson's reagent) in appropriate solvents or under solvent-free condition (see Reference Example 244).
    • [Step 3]
  • The compound (16) can be prepared by performing a cyclization reaction on the compound (15) according to a conventional reaction. For example, the reaction can be achieved by reacting the compound (15) with Ar2—C(═O)NHNH2, Lewis acids (for example, trimethylsilyl triflate) or metal acid compounds (for example, silver trifluoroacetate) in appropriate solvents or under solvent-free condition. However, if Z2 in the compound (15) represents —C(═O)ORb2, the Z2 is preferably converted into —C(═O)NRcRd via an amination reaction before cyclization reaction (see Reference Example 409).
  • With respect to the case where the Present compound represented by formula (I), or intermediate compounds or starting materials therefor contain a functional group, some examples of optional conversion reaction are illustrated as aforementioned. However, without limiting to such illustrated examples, a substituent introduction reaction or a functional group transformation reaction or the others can be carried out according to a conventional method for a person skilled in the art. As examples of such reaction, the methods described in “Experimental Chemistry (Edited by Chemical Society in Japan, published by Maruzen)” or “Comprehensive Organic Transformations, edited by Larock R. C. (VCH publishers, Inc., 1989)” or the others can be used. Examples of the functional group transformation reaction include a carbon-carbon binding reaction (for example, Friedel-Crafts reaction or wittig reaction), a reductive amination reaction or a carbon-nitrogen binding reaction (for example, an alkylation of amine), an oxidation reaction or a reduction reaction and the others.
  • Also, when the present compound represented by formula (I) or intermediate compound therefor contains a functional group (for example, amino, carboxyl, hydroxy or oxo), if necessary, a protection reaction or a deprotection reaction may be carried out. Examples of preferred protective group, a protection method and a deprotection method are described in detail in “Protective Groups in Organic Synthesis 4th Edition (John Wiley & Sons, Inc.; 2007)” and the others.
  • The compound (I) that prepared in each of the above-mentioned processes can be isolated or purified according to a conventional method (for example, chromatography, recrystallization or reprecipitation). Also, the compound of formula (I) or pharmacologically acceptable salts thereof may form an axial chirality (i.e., atropisomer) or may contain a substituent having an asymmetric carbon, and an optical isomer may be existed in such compounds. The Present compound encompasses a mixture or an isolates of each isomer. Examples of the method for preparing such optical isomer in pure form include optical resolutions (for example, chromatography with optically active column, preferential crystallization or diastereomeric resolution).
  • As for optical resolution, when the Present compound or intermediate compound therefor contains a basic functional group, they may form salts with optical active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxy alanine and lactic acid; dicarboxylic acids such as tartalic acid, o-diisopropylidene tartalic acid and malic acid; and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) in an inert solvent (for example, alcohols such as methanol, ethanol and 2-propanol; ethers such as diethyl ether; esters such as ethyl acetate; aromatic hydrocarbons such as toluene; acetonitrile; and mixed solvents thereof.
  • Also, when the Present compound or intermediate compound therefor contains an acidic substituents such as carboxyl group or sulfonic acid group, they may form salts with optical active bases (for example, α-phenethylamine, kinin, quinidine, cinchonidine, cinchonine, strychnine, cis-2-benzylaminocyclohexanemethanol or organic amines (for example, amino acids)). The temperature at forming the salt includes, for example, a range of room temperature to a boiling point of the solvent used (including water). In order to increase an optical purity, it is desirous to raise the reaction temperature once to near the boiling point of the solvent. If necessary, the precipitated salts are cooled before a collection with filtering so as to improve a yield. The amount of optical active acid or amine is appropriately within a range of about 0.5 to about 2.0 equivalents, preferably around 1 (one) equivalent as opposed to that of substrate used. If necessary, the crystals are recrystallized in an inert solvent (for example, alcohols such as methanol, ethanol and 2-propanol; ethers such as diethyl ether; esters such as ethyl acetate; aromatic hydrocarbons such as toluene; acetonitrile; and mixed solvents thereof) so as to obtain optical active salts with high purity. If necessary, the obtained salts may be treated with acids or bases according to a conventional method so as to obtain free products.
  • The compound (I) may be obtained in the form of free base or acid addition salts depending on the kind of functional group present in the structure, a selection of starting materials or a condition for reaction treatment and the resultant compounds can be converted into the compound of formula (I) according to a conventional method. Also, the compound of formula (I) can be treated with various acids according to a conventional method to be derivatized to acid addition salts.
  • The uracil derivative of the present invention has strong neutrophilelastase inhibitory activity as below-mentioned, and thus is expected to being useful medicinal drug for diseases that are desirous for and/or required for elastase inhibitory activity. The administration route of the Present compound may be either oral administration, parenteral administration or intrarectal administration, and the daily dose may vary depending on the kind of the compound, the administration method, and the condition or ages of the patients. For example, for oral administration, the dose is usually within a range of about 0.01 to 3,000 mg, preferably about 0.1 to 500 mg per 1 kg human or mammal, and can be administered once daily or in divided doses. For example, for parenteral administration such as intravenous injection, the dose is usually within a range of about 0.01 to 500 mg, preferably about 1 to 100 mg per 1 kg human or mammal, and can be administered once daily or in divided doses.
  • When the Present compound is used as the above-mentioned medicinal use, said compound is administered in the form of pharmaceutical formulations that are prepared by mixing with carriers for pharmaceutical formulation. The carriers for formulation may be used as non-toxic substances that are commonly used in the pharmaceutical formulation arts and also are not reactive with the Present compound. Specific examples of carriers for pharmaceutical formulation include citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partly pregelatinized starch, sucrose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, magnesium aluminometa silicate, synthetic aluminum silicate, crystalline cellulose, carboxymethyl cellulose sodium, hydroxypropylstarch, carboxymethyl cellulose potassium, ion exchange resin, methyl cellulose, gelatin, gum arabic, pullulan, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, Veegum (trade mark), carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerine, glycerin-fatty acid ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid, water and the others.
  • Examples of the pharmaceutical formulations include tablets, capsules, granules, powders, syrups, suspensions, injectable solutions, suppositories, eye-drops, ointments, liniments, patches, inhalations and the others. Such formulations can be prepared according to a conventional method. As for liquid formulations, the formulations may be in a form that the compounds are solved or suspended in water or other appropriate media at time of use. Also, the tablets and granules may be coated according to a well-known method. Moreover, such formulations may further contain other ingredients with therapeutic values.
  • The present compound or physiologically acceptable salts thereof have an elastase inhibitory activity, and can be thus used as elastase inhibitors, or a therapeutic agent or a prophylactic agent for diseases associated with elastase. Examples of the diseases in which elastase is suggested to associate with pathological conditions include inflammatory disease, specifically chronic obstructive pulmonary disease (COPD), pulmonarycystic fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic interstitial pneumonia (IIP) including idiopathic pulmonary fibrosis (IPF), chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplantation, premature rupture of membrane, bullosa, shock, sepsis, systemic lupus erythematodes (SLE), Crohn disease, disseminated intravascular coagulation (DIC), ischemia-reperfusion induced-tissue injury, corneal scar tissue formation, myelitis, lung squamous cell carcinoma, pulmonary adenocarcinoma, lung cancers such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colorectal cancer, skin cancer, pancreas cancer, glioma and the others.
  • For treatment for the above-mentioned diseases that required for elastase inhibitory activities, the Present compound or physiologically acceptable salts thereof (or pharmaceutically acceptable salts), or a pharmaceutical composition or pharmaceutical preparations comprising the Present compound may be administered in combination with the below-mentioned therapeutic agent or prophylactic agent.
  • Specific examples of therapeutic agent or prophylactic agent that may be used in combination include the followings: a short-lasting or long-lasting muscarinic receptor (subtypes M1, M2 and M3) antagonists (for example, ipratropium bromide and tiotropium bromide); a short-lasting or long-lasting β receptor (subtypes β1, β2, β3 and β4) agonist (for example, fenoterol hydrobromide, salbutamol sulfate, salmeterol xinafoate or formoterol fumarate); inhaled or oral steroids (for example, fluticasone propionate, beclometasone propionate or budesonide); combination drugs of β receptor agonists and inhaled steroids (for example, combination drug of salmeterol xinafoate and fluticasone propionate); phosphodiesterase (PDE) inhibitors (for example, PDE4 inhibitors such as methylxanthine (including theophylline, aminophylline and the others); expectorans (for example, carbocysteine); and antibiotics (for example, erythromycin or clarithromycin) and the others.
  • The present compound or physiologically acceptable salts thereof may be administered prior to, simultaneously with or after the above-mentioned therapeutic agent or prophylactic agent that may be used in combination to human or mammal.
    • EXAMPLES
  • Hereinafter, the present invention is explained in more detail with some Reference Examples, Examples and Test Examples, but the present invention should not be construed to be limited thereto. The compounds were identified by elemental analysis value, mass spectrum, high performance liquid chromatography-mass spectrometer; LC-MS, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the others.
  • Hereinafter, the following abbreviations are sometimes used in Reference Example, Example and the tables described in the Example to simplify the description of the specification.
  • The abbreviations to be used as substituent include the followings: Me: methyl, Et: ethyl, Ph: phenyl, CN: cyano, Bn: benzyl, NO2: nitro, n-Pr: normal propyl, i-Pr: isopropyl, c-Pr: cyclopropyl, t-Bu: tert-butyl, Ac: acetyl, Cbz: benzyloxycarbonyl, Boc: tert-butyloxycarbonyl, TBDPS: tert-butyldiphenylsilyl, Ms: methanesulfonyl, IPA: isopropyl alcohol. Also, eutomer (abbreviation “e”) means an optical isomer having high physiological activity, and distomer (abbreviation “d”) means an optical isomer having low physiological activity. Also, the symbol representing enantiomeric excess is expressed as “ee”, and the symbol representing diastereomeric excess is expressed as “de”. With respect to the symbols to be used in NMR include the followings: s: singlet, d: doublet, dd: double doublet, t: triplet, td: triple doublet, q: quartet, quint: quintet, sept: septet, m: multiplet, br: broad, brs: broad singlet, brd: broad doublet, brt: broad triplet, and J: coupling constant.
  • The measurement conditions in NMR are as follows:
  • Measurement condition 1: 300 MHz, CDCl3
  • Measurement condition 2: 300 MHz, DMSO-d6
  • Measurement condition 3: 300 MHz, CD3OD
  • Measurement condition 4: 400 MHz, CDCl3
  • Measurement condition 5: 400 MHz, DMSO-d6
  • Measurement condition 6: 400 MHz, CD3OD
  • high performance liquid chromatography-mass spectrometer; a measurement condition for LC-MS is shown below (measurement conditions 7, 8 and 9) and the observed values by mass analysis [MS (m/z)] is expressed as MH+ and the retention time is expressed as Rt (min.).
  • Measurement condition 7:
  • Detector: LC/MS-2010EV (manufactured by SHIMAZU CO.)
  • HPLC: LC/MS-2010C HT (manufactured by SHIMAZU CO.)
  • Column: CAPCELL PAK, C18 MGII (manufactured by SHISEIDO CO.) (S-3 μm, 4.6×35 mm)
  • Solvent: A solution; acetonitrile, B solution; 0.05% trifluoroacetic acid/water,
  • Elution condition:
  • 0.0-5.0 (min.); A/B=10:90→99:1
  • 5.0-7.0 (min.); A/B=99:1
  • 7.01-10.0 (min.); A/B=10:90
  • Flow rate: 0.35 ml/min.
  • UV: 220 nm
  • Column temperature: 40° C.
  • Measurement condition 8:
  • MS detector: Waters micromass ZQ
  • HPLC: Waters 2790 separations module
  • Column: Impact Cadenza CD-C18 2.0 mm×20 mm
  • Flow rate: 1.0 ml/min.
  • detection wavelength: 254 nm
  • Mobile phase:
  • A solution; water
  • B solution; acetonitrile
  • C solution; 2% formic acid acetonitrile solution
  • Elution Condition:
  • 0.0-0.1 (min.); A solution:B solution:C solution=95:2:3
  • 0.1-3.1 (min.); A solution:B solution:C solution=95:2:3→1:96:3
  • 3.1-3.5 (min.); A solution:B solution:C solution=1:96:3
  • Measurement condition 9:
  • MS DETECTOR: ACQUITY (trade mark) SQ Detector (Waters)
  • HPLC: ACQUITY UPLC (trade mark)
  • Column: ACQUITY UPLC (trade mark) BEH C18 1.7 μm 2.1×30 mm Column
  • Flow rate: 0.8 ml/min.
  • Detection wavelength: 254 nm
  • Mobile phase:
  • A; 0.06% formic acid water
  • B; 0.06% formic acid acetonitrile
  • Elution condition:
      • 0-1.3 min.; A:B=98:2→A:B=4:96
      • 1.3-1.5 min.; A:B=4:96→A:B=98:2
    Reference Examples 1-18
  • The compounds 1a indicated in the below-mentioned table (Reference Examples 1-18) were prepared according to the process described in Journal of Medicinal Chemistry, 2004, 47(7), 1617-1630 and the others.
  • Figure US20140179670A1-20140626-C00056
  • TABLE 1
    Ref Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    1
    Figure US20140179670A1-20140626-C00057
    Figure US20140179670A1-20140626-C00058
         		1 1.24 (t, 3H. J = 6.9 Hz), 2.58 (t, 2H, J = 5.7 Hz), 3.54 (dt, 2H, J = 6.0, 5.7 Hz), 4.15 (q, 2H, J = 7.5 Hz), 5.54 (brs, 1H), 6.99 (brs, 1H), 7.27 (d, 1H, J = 7.8 Hz), 7.36 (dd, 1H, J = 8.1, 7.8 Hz), 7.52 (d, 1H, J = 2.4 Hz), 7.61 (s, 1H)
    2
    Figure US20140179670A1-20140626-C00059
    Figure US20140179670A1-20140626-C00060
         		1 1.24 (t, 3H, J = 7.2 Hz), 1.87 (quin, 2H, J = 6.6 Hz), 2.39 (t, 2H, J = 6.6 Hz), 3.31 (dd, 2H, J = 6.9, 6.3 Hz), 4.14 (q, 2H, J = 7.2 Hz), 7.37 (t, 1H, J = 8.1 Hz), 7.56-7.66 (m, 3H)
    3
    Figure US20140179670A1-20140626-C00061
    Figure US20140179670A1-20140626-C00062
         		1 4.10 (d, 2H, J = 5.5 Hz), 5.19 (s, 2H), 5.42 (brs, 1H), 6.88 (brs, 1H), 7.24-7.34 (m, 7H), 7.42 (d, 1H, J = 8.4 Hz), 7.61 (s, 1H)
    4
    Figure US20140179670A1-20140626-C00063
    Figure US20140179670A1-20140626-C00064
         		1 3.40-3.47 (m, 8H), 4.40 (t, 1H, J = 4.6 Hz), 5.44 (brs, 1H), 7.21 (d, 1H, J = 7.7 Hz), 7.31 (t, 1H, J = 8.1 Hz), 7.45 (d, 1H, J = 8.3 Hz), 7.57 (s, 1H)
    5
    Figure US20140179670A1-20140626-C00065
    Figure US20140179670A1-20140626-C00066
         		1 1.31-1.55 (m, 15H), 2.67 (t, 1H, J = 6.6 Hz), 3.06-3.14 (m, 2H), 3.21-3.27 (m, 2H), 4.75 (brs, 1H), 5.63 (brs, 1H), 7.19 (d, 1H, J = 7.5 Hz), 7.34 (t, 1H, J = 7.8 Hz), 7.60 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz)
    6
    Figure US20140179670A1-20140626-C00067
    Figure US20140179670A1-20140626-C00068
         		1 3.77 (s, 3H), 4.37 (d, 2H, J = 5.1 Hz), 4.94 (brs, 1H), 6.54 (brs, 1H), 6.86 (dd, 2H, J = 6.6, 1.8 Hz), 7.21-7.27 (rn, 3H), 7.36 (t, 1H, J = 7.8 Hz), 7.50 (d, 1H, J = 7.2 Hz), 7.58 (s, 1H)
    7
    Figure US20140179670A1-20140626-C00069
    Figure US20140179670A1-20140626-C00070
         		4 2.91 (s, 3H), 7.35 (dt, 1H, J = 1.3, 8.0 Hz), 7.41 (t, 1H, J = 8.0 Hz), 7.61 (ddd, 1H, J = 1.3, 1.8, J = 8.0 Hz), 7.73 (t, 1H, J = 1.8 Hz)
    8
    Figure US20140179670A1-20140626-C00071
    Figure US20140179670A1-20140626-C00072
         		4 2.85 (s, 3H), 3.90 (s, 3H), 5.18 (brs, 1H), 7.10 (s, 1H), 7.37 (t, 1H, J = 7.9 Hz), 7.68-7.73 (m, 2H), 7.89 (t, 1H, J = 1.9 Hz)
    9
    Figure US20140179670A1-20140626-C00073
    Figure US20140179670A1-20140626-C00074
         		1 1.28 (s, 9H), 2.81 (d, 3H, J = 3.9 Hz), 4.77 (brs, 1H), 6.37 (brs, 1H), 7.08-7.4 (m, 2H), 7.22-7.27 (m, 2H)
  • TABLE 2
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    10
    Figure US20140179670A1-20140626-C00075
    Figure US20140179670A1-20140626-C00076
         		1 2.96 (d, 3H, J = 4.8 Hz), 6.97 (d, 1H, J = 8.1 Hz), 7.21 (brs, 1H), 7.73 (t, 1H, J = 7.8 Hz), 8.53 (brs, 1H), 8.86 (brs, 1H)
    11
    Figure US20140179670A1-20140626-C00077
         		iPr 1 1.18 (d, 6H, J = 6.3 Hz), 1.40 (d, 1H, J = 6.6 Hz), 7.27 (s, 1H), 7.37 (t, 1H, J = 7.5 Hz), 7.50 (d, 1H, J = 8.4 Hz), 7.60 (s, 1H)
    12
    Figure US20140179670A1-20140626-C00078
    Figure US20140179670A1-20140626-C00079
         		1 1.66-1.75 (m, 2H), 1.78-1.88 (m, 2H), 2.32-2.41 (m, 2H), 4.24 (sept, 1H, J = 7.8 Hz), 4.83 (brs, 1H), 6.42 (brs, 1H), 7.26 (s, 1H), 7.37 (t, 1H, J = 7.8 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.59 (s, 1H)
    13
    Figure US20140179670A1-20140626-C00080
    Figure US20140179670A1-20140626-C00081
         		1 3.77 (dd, 2H, J = 9.6, 4.8 Hz), 4.34 (dd, 2H, J = 9.3, 7.5 Hz), 4.57 (d, 1H, J = 7.2 Hz), 5.09 (s, 2H), 5.31 (d, 1H, J = 7.8 Hz), 6.82 (s, 1H), 7.26-7.32 (m, 6H), 7.37 (t, 1H, J = 7.5 Hz), 7.50 (d, 1H, J = 8.7 Hz), 7.61 (s, 1H)
    14
    Figure US20140179670A1-20140626-C00082
    Figure US20140179670A1-20140626-C00083
         		1 1.30 (t, 3H, J = 6.3 Hz), 1.43 (d, 3H, J = 7.5 Hz), 4.23 (q, 2H, J = 6.9 Hz), 4.50-4.57 (m, 1H), 5.69 (brs, 1H), 7.07 (brs, 1H), 7.18 (d, 1H, J = 7.5 Hz), 7.24-7.30 (m, 1H), 7.38 (d, 1H, J = 7.5 Hz), 7.59 (s, 1H)
    15
    Figure US20140179670A1-20140626-C00084
    Figure US20140179670A1-20140626-C00085
         		1 1.16 (d, 3H, J = 6.9 Hz), 3.45-3.54 (in, 1H), 3.71 (dd, 1H, J = 10.8, 3.3 Hz), 3.95-3.99 (m, 1H), 7.25 (s, 1H), 7.35 (t, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 8.7 Hz), 7.59 (s, 1H)
    16
    Figure US20140179670A1-20140626-C00086
    Figure US20140179670A1-20140626-C00087
         		1 1.19 (d, 3H, J = 6.6 Hz), 2.07 (s, 3H), 3.97 (dd, 1H, J = 10.5, 4.2 Hz), 4.07-4.21 (m, 2H), 4.96 (d, 1H, J = 7.2 Hz), 6.94 (brs, 1H). 7.24-7.26 (m, 1H), 7.33 (t, 1H, J = 7.8 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.62 (s, 1H)
    17
    Figure US20140179670A1-20140626-C00088
    Figure US20140179670A1-20140626-C00089
         		4 1.42 (d, 3H, J = 6.9 Hz), 4.89 (dq, 1H, J = 6.9, 6.9 Hz), 5.55 (d, 1H, J = 6.9 Hz), 7.12 (s, 1H), 7.19-7.33 (m, 7H), 7.37 (d, 1H, J = 8.2 Hz), 7.49 (s, 1H)
    18
    Figure US20140179670A1-20140626-C00090
    Figure US20140179670A1-20140626-C00091
         		3 3.30-3.34 (m, 2H), 3.63 (t, 2H, J = 5.4 Hz), 7.22 (d, 1H, J = 7.5 Hz), 7.41 (t, 1H, J = 8.1 Hz), 7.51 (d, 1H, J = 8.7 Hz), 7.83 (s, 1H)
    • Reference Example 19
  • Acetic acid 2-(3-(3-(trifluoromethyl)phenyl)ureido)ethyl ester was obtained by using the compound of Reference Example 18 according to a known method.
  • Figure US20140179670A1-20140626-C00092
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.07 (d, 3H, J=3.3 Hz), 3.51-3.54 (m, 2H), 4.20 (dt, 2H, J=5.1, 3.0 Hz), 7.27 (d, 1H, J=9.9 Hz), 7.38 (dt, 1H, J=7.5, 3.6 Hz), 7.51 (d, 1H, J=2.5 Hz), 5.60 (s, 1H)
    • Reference Examples 20-51
  • The compounds (1b) indicated in the below-mentioned table (Reference Examples 20-51) were prepared by using the compounds of Reference Examples 1-19 and well-known compounds according to the process described in Heterocycles 1993, 36(2), 307-314.
  • Figure US20140179670A1-20140626-C00093
  • TABLE 3
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    20
    Figure US20140179670A1-20140626-C00094
    Figure US20140179670A1-20140626-C00095
         		1 1.80 (d, 3H, J = 0.6 Hz), 3.30 (s, 3H), 5.77 (d, 1H, J = 0.9 Hz), 7.40 (d. 1H, J = 7.5 Hz), 7.46 (s, 1H), 7.61 (t, 1H, J = 7.8 Hz), 7.71 (d, 1H, J = 7.8 Hz)
    21
    Figure US20140179670A1-20140626-C00096
    Figure US20140179670A1-20140626-C00097
         		2 0.85 (t, 3H, J = 7.4 Hz), 1.51-1.57 (m, 2H), 1.77 (s, 3H), 3.73 (t, 2H, J = 7.4 Hz), 5.81 (s, 1H), 7.74-7.75 (m, 2H), 7.84-7.85 (m, 1H), 7.93 (s, 1H)
    22
    Figure US20140179670A1-20140626-C00098
    Figure US20140179670A1-20140626-C00099
         		1 1.26 (t, 3H, J = 6.9 Hz), 1.87 (d, 3H, J = 0.9 Hz), 4.21 (q, 2H, J = 7.2 Hz), 4.68 (d, 2H, J = 1.8 Hz), 5.79 (d, 1H, J = 0.9 Hz), 7.47 (d, 1H, J = 8.1 Hz), 7.53 (s, 1H), 7.64 (t, 1H, J = 8.1 Hz), 7.75 (d, 1H, J = 8.1 Hz)
    23
    Figure US20140179670A1-20140626-C00100
    Figure US20140179670A1-20140626-C00101
         		1 1.22 (t, 3H, J = 7.2 Hz), 1.84 (d, 3H, J = 0.9 Hz), 2.66 (t, 2H, J = 7.5 Hz), 4.11 (q, 2H, J = 7 .2 Hz), 4.24 (t, 2H, J = 7.2 Hz), 5.73 (d, 1H, J = 0.9 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.51 (s, 1H), 7.65 (t, 1H, J = 8.1 Hz), 7.75 (d, 1H, J = 7.8 Hz)
    24
    Figure US20140179670A1-20140626-C00102
    Figure US20140179670A1-20140626-C00103
         		1 1.21 (t, 3H, J = 7.2 Hz), 1.83 (d, 3H, J = 0.6 Hz), 1.97 (quin, 2H, J = 6.3 Hz), 2.36 (t, 2H, J = 7.5 Hz), 3.99 (t, 2H, J = 6.9 Hz), 4.10 (q, 2H, J = 6.9 Hz), 5.72 (d, 1H, J = 0.9 Hz), 7.31-7.56 (m, 2H), 7.64 (t, 1H. J = 8.1 Hz), 7.74 (d, 1H, J = 7.8 Hz)
    25
    Figure US20140179670A1-20140626-C00104
    Figure US20140179670A1-20140626-C00105
         		1 1.88 (s, 3H), 4.76 (s, 2H), 5.19 (s, 2H), 5.81 (s, 1H), 7.31-7.37 (m, 5H), 7.45 (d, 1H, J = 7.8 Hz), 7.53 (s, 1H), 7.66 (t. 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 7.8 Hz)
    26
    Figure US20140179670A1-20140626-C00106
    Figure US20140179670A1-20140626-C00107
         		1 1.86 (s, 3H), 3.37 (s, 6H), 4.12 (d, 2H, J = 5.7 Hz), 4.84 (t, 1H, J = 5.7 Hz), 5.76 (s, 1H), 7.47 (d, 1H, J = 7.9 Hz), 7.54 (s, 1H), 7.67 (t, 1H, J = 7.9 Hz), 7.76 (d, 1H, J = 7.9 Hz)
  • TABLE 4
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    27
    Figure US20140179670A1-20140626-C00108
    Figure US20140179670A1-20140626-C00109
         		1 1.30-1.38 (m, 2H), 1.41 (s, 9H), 1.46-1.52 (m, 2H), 1.60-1.68 (m, 2H), 1.83 (s, 3H), 3.03-3.11 (m, 2H), 3.91 (t. 2H, J = 7.6 Hz), 4.51 (brs, 1H), 5.72 (s. 1H), 7.44 (d, 1H, J = 7.9 Hz), 7.52 (s, 1H), 7.65 (t, 1H, J = 7.9 Hz), 7.74 (d, 1H, J = 7.9 Hz)
    28
    Figure US20140179670A1-20140626-C00110
    Figure US20140179670A1-20140626-C00111
         		1 1.81 (d, 3H, J = 0.9 Hz), 3.76 (s, 3H), 5.04 (s, 2H), 5.74 (d, 1H, J = 0.9 Hz), 6.78-6.83 (m. 2H), 7.39-7.49 (m, 4H), 7.36 (t, 1H, J = 1.8 Hz), 7.73 (d, 1H, J = 7.8 Hz)
    29
    Figure US20140179670A1-20140626-C00112
    Figure US20140179670A1-20140626-C00113
         		4 1.89 (d, 3H, J = 0.8 Hz), 3.38 (s, 3H), 5.80 (d, 1H, J = 0.8 Hz), 7.53 (ddd, 1H, J = 1.3, 1.7, 7.9 Hz), 7.60 (t, 1H, J = 1.7 Hz), 7.69 (t, 1H, J = 7.9 Hz), 7.82 (dt, 1H, J = 1.3, 7.9 Hz)
    30
    Figure US20140179670A1-20140626-C00114
    Figure US20140179670A1-20140626-C00115
         		4 1.80 (d, 3H, J = 0.8 Hz), 3.30 (s, 3H), 3.87 (s, 3H), 5.69 (d, 1H, J = 0.8 Hz), 7.38 (ddd, 1H, J = 1.3, 1.8, 7.9 Hz), 7.55 (t, 1H, J = 7.9 Hz), 7.86 (t, 1H, J = 1.8 Hz), 8.10 (dt, 1H, J = 1.3, 7.9 Hz)
    31
    Figure US20140179670A1-20140626-C00116
    Figure US20140179670A1-20140626-C00117
         		4 1.91 (d, 3H, J = 0.8 Hz). 3.38 (s, 3H), 5.77 (d, 1H, J = 0.8 Hz), 7.01 (dt, 1H, J = 2.2, 8.6 Hz), 7.05-7.08 (m, 1H), 7.23 (ddt, 1H, J = 0.8, 1.6, 8.4 Hz), 7.51 (dt, 1H, J = 6.2, 8.2 Hz)
    32
    Figure US20140179670A1-20140626-C00118
    Figure US20140179670A1-20140626-C00119
         		4 1.92 (d, 3H, J = 0.8 Hz), 3.38 (s, 3H), 3.85 (s, 3H), 5.75 (d, 1H, J = 0.8 Hz), 6.77 (t, 1H, J = 2.2 Hz), 6.83 (ddd, 1H, J = 0.8, 1.9, 7.8 Hz), 7.03 (ddd, 1H, J = 0.8, 2.2, 8.5 Hz), 7.43 (t, 1H, J = 8.1 Hz)
    33
    Figure US20140179670A1-20140626-C00120
    Figure US20140179670A1-20140626-C00121
         		4 1.81 (d, 3H, J = 0.8 Hz), 3.29 (s, 3H), 5.71 (d, 1H, J = 0.8 Hz), 7.31 (t, 1H, J = 9.1 Hz), 7.36-7.41 (m, 1H), 7.44-7.47 (m, 1H)
  • TABLE 5
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    34
    Figure US20140179670A1-20140626-C00122
    Figure US20140179670A1-20140626-C00123
         		1 1.81 (d, 3H, J = 0.9 Hz), 3.34 (s, 3H), 5.75 (d, 1H, J = 0.9 Hz), 7.35 (d, 1H, J = 7.5 Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.72 (t, 1H, J = 6.3 Hz), 7.84 (d, 1H, J = 6.6 Hz)
    35
    Figure US20140179670A1-20140626-C00124
    Figure US20140179670A1-20140626-C00125
         		1 1.85 (d, 3H, J = 0.9 Hz), 3.34 (s, 3H), 5.75 (s, 1H), 7.38 (d, 2H, J = 8.4 Hz), 7.79 (d, 2H, J = 8.7 Hz)
    36
    Figure US20140179670A1-20140626-C00126
    Figure US20140179670A1-20140626-C00127
         		1 1.86 (d, 3H, J = 0.9 Hz), 3.29 (s, 3H), 5.72 (d, 1H, J = 0.6 Hz), 7.57 (d, 1H, J = 1.8 Hz), 7.77 (d, 1H, J = 7.8 Hz), 8.05 (t, 1H, J = 8.1 Hz)
    37
    Figure US20140179670A1-20140626-C00128
    Figure US20140179670A1-20140626-C00129
         		1 1.32 (d, 3H, J = 0.9 Hz), 3.29 (s, 3H), 5.68 (d, 1H, J = 0.9 Hz), 7.11-7.14 (m, 1H), 7.31- 7.36 (m, 2H), 7.55-7.58 (m, 1H)
    38
    Figure US20140179670A1-20140626-C00130
    Figure US20140179670A1-20140626-C00131
         		1 1.86 (d, 3H, J = 0.9 Hz), 3.33 (s, 3H), 5.72 (d, 1H, J = 0.6 Hz), 7.11-7.14 (m, 1H), 7.24- 7.25 (m, 1H), 7.43-7.45 (m, 2H)
    39
    Figure US20140179670A1-20140626-C00132
    Figure US20140179670A1-20140626-C00133
         		1 1.87 (d, 3H, J = 0.9 Hz), 3.34 (s, 3H), 5.78 (s, 1H), 7.57-7.61 (m, 1H), 7.72 (t, 1H, J = 8.1 Hz), 8.14 (t, 1H, J = 2.1 Hz), 8.34-8.37 (m, 1H)
    40
    Figure US20140179670A1-20140626-C00134
    Figure US20140179670A1-20140626-C00135
         		1 1.85 (d, 3H, J = 0.9 Hz), 2.38 (s, 3H), 3.34 (s. 3H), 5.70 (d, 1H, J = 0.9 Hz), 6.99-7.01 (m, 2H), 7.27 (s, 1H), 7.37 (t, 1H, J = 7.2 Hz)
    41
    Figure US20140179670A1-20140626-C00136
    Figure US20140179670A1-20140626-C00137
         		1 1.31 (s, 9H), 1.82 (s, 3H), 3.35 (s, 3H), 5.71 (s, 1H), 7.00-7.02 (m, 1H), 7.17 (t, 1H, J = 1.5 Hz), 7.38-7.49 (m, 2H)
    42
    Figure US20140179670A1-20140626-C00138
    Figure US20140179670A1-20140626-C00139
         		1 1.85 (d, 3H, J = 0.9 Hz), 3.10 (s, 3H), 3.34 (s, 3H), 5.77 (d, 1H, J = 0.9 Hz), 7.53 (ddd, 1H, J = 7.8, 2.1, 0.9 Hz), 7.74 (t, 1H, J = 7.8 Hz), 7.84 (t, 1H, J = 2.1 Hz), 8.03-8.06 (m, 1H)
  • TABLE 6
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    43
    Figure US20140179670A1-20140626-C00140
         		Et 1 1.23 (t, 3H, J = 7.2 Hz), 1.83 (d, 3H, J = 0.9 Hz), 3.99 (q, 2H, J = 6.9 Hz), 5.73 (s, 1H), 7.44 (d, 1H, J = 7.5 Hz), 7.52 (s, 1H), 7.65 (t, 1H, J = 7.5 Hz), 7.73 (d, 1H, J = 8.1 Hz)
    44
    Figure US20140179670A1-20140626-C00141
         		iPr 1 1.45 (d, 6H, J = 6.9 Hz), 1.80 (d, 3H, J = 0.3 Hz), 5.18 (quintet, 1H, J = 6.9 Hz), 5.68 (s, 1H), 7.44 (d, 1H, J = 7.8 Hz), 7.51 (s, 1H), 7.64 (t, 1H, J = 7.8 Hz), 7.73 (d, 1H, J = 7.8 Hz)
    45
    Figure US20140179670A1-20140626-C00142
         		cPr 1 0.74-0.85 (m, 2H), 1.07-1.14 (m, 2H), 1.81 (s, 3H), 2.65-2.73 (m, 1H), 5.96 (d, 1H, J = 0.9 Hz), 7.42 (d, 1H, J = 8.1 Hz), 7.50 (s, 1H), 7.64 (t, 1H, J = 8.1 Hz), 7.73 (d, 1H, J = 7.8 Hz)
    46
    Figure US20140179670A1-20140626-C00143
    Figure US20140179670A1-20140626-C00144
         		1 1.65-1.90 (m, 5H), 2.16-2.25 (m, 2H), 2.91 (dseptet, 2H, J = 9.6, 1.8 Hz), 5.28 (septet, 1H, J = 8.7 Hz), 5.68 (s, 1H), 7.44 (d, 1H, J = 8.1 Hz), 7.51 (s, 1H), 7.65 (t, 1H, J = 7.8 Hz), 7.73 (d, 1H, J = 7.8 Hz)
    47
    Figure US20140179670A1-20140626-C00145
    Figure US20140179670A1-20140626-C00146
         		1 1.83 (d, 3H, J = 0.9 Hz), 4.25 (t, 2H, J = 9.0 Hz), 4.50 (dd, 2H, J = 9.0, 6.3 Hz), 5.06 (s, 2H), 5.36-5.46 (m, 1H), 5.71 (d, 1H, J = 9.0 Hz), 7.25-7.33 (m, 5H), 7.43 (d, 1H, J = 8.1 Hz), 7.50 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 7.8 Hz)
    48
    Figure US20140179670A1-20140626-C00147
    Figure US20140179670A1-20140626-C00148
         		1 1.16 (dt, 3H, J = 7.2, 0.9 Hz), 1.52 (d, 3H, J = 6.9 Hz), 1.80 (s, 3H), 4.04-4.17 (m, 2H), 5.41 (dq, 1H, J = 6.9, 2.4 Hz), 5.69 (d, 1H, J = 0.9 Hz), 7.36-7.49 (m, 2H), 7.59 (t, 1H, J = 8.1 Hz), 7.68 (d, 1H, J = 8.1 Hz)
    49
    Figure US20140179670A1-20140626-C00149
    Figure US20140179670A1-20140626-C00150
         		1 1.47 (d, 3H, J = 7.2 Hz), 1.83 (d, 3H, J = 0.6 Hz), 2.01 (d, 3H, J = 0.3 Hz), 4.26-4.35 (m, 1H), 4.65 (dq, 1H, J = 10.8, 8.4 Hz), 5.25 (brs, 1H), 5.70 (s, 1H), 7.40-7.55 (m, 2H), 7.65 (t, 1H, J = 7.8 Hz), 7.74 (d, 1H, J = 8.1 Hz)
    50
    Figure US20140179670A1-20140626-C00151
    Figure US20140179670A1-20140626-C00152
         		4 1.82 (s, 3H), 1.87 (d, 3H, J = 7.1 Hz), 5.74 (s, 1H), 6.31 (q, 1H, J = 6.8 Hz), 7.22-7.34 (m, 3.5H), 7.45-7.48 (m, 3H), 7.53 (s, 0.5H), 7.60-7.68 (m, 1H), 7.70-7.73 (m, 1H)
    51
    Figure US20140179670A1-20140626-C00153
    Figure US20140179670A1-20140626-C00154
         		1 1.85 (d, 3H, J = 0.9 Hz), 1.99 (s, 3H), 4.20-4.24 (m, 2H), 4.31-4.36 (m, 2H), 5.74 (s, 1H), 7.44 (d, 1H, J = 7.5 Hz), 7.52 (s, 1H), 7.65 (t, 1H, J = 7.8 Hz), 7.44 (d. 1H, J = 8.1 Hz)
    • Reference Examples 52-53
  • Figure US20140179670A1-20140626-C00155
    • Step 1 Reference Example 52
  • To a solution of 6-amino-1-(3-trifluoromethylphenyl)-pyrimidin-2,4-(1H,3H)-dione (3.0 g) (prepared according to the method described in Bioorganic & Medicinal Chemistry 2003, 11(23), 4933-4940) in methanol (75.0 ml) was added N,N-dimethylformamide dimethylacetal (3.9 g) and the resulting mixture was stirred with heating under reflux for two hours. The precipitated solids were collected by filtration with methanol to afford N′-[2,6-dioxo-3-(3-trifluorophenyl)-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformimidamide (1.8 g).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.62 (s, 3H), 3.04 (s, 3H), 5.09 (d, 1H, J=2.2 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.49 (s, 1H), 7.53 (t, 1H, J=7.8 Hz), 7.58-7.62 (m, 2H), 7.85 (s, 1H)
    • Step 2 Reference Example 53
  • To a solution of N′-[2,6-dioxo-3-(3-trifluorophenyl)-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformimidamide (600 mg), potassium carbonate (508.0 mg) in N,N-dimethy formamide (5.0 ml) was added methyl iodide (340 μl) and the resulting mixture was stirred at 80° C. for six hours. The reaction mixture was poured into ice water and the precipitated solids were collected by filtration with water to afford N,N-dimethyl-N′-[1-methyl-2,6-dioxo-3-(3-trifluorophenyl)-1,2,3,6-tetrahydropyrimidin-4-yl]formimidamide (550.0 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.61 (s, 3H), 3.02 (s, 3H), 3.35 (s, 3H), 5.18 (s, 1H), 7.39 (d, 1H, J=7.7 Hz), 7.47 (s, 1H), 7.52 (t, 1H, J=7.7 Hz), 7.58-7.61 (m, 2H)
    • Reference Example 54
  • The below-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 53.
  • Figure US20140179670A1-20140626-C00156
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 0.85 (t, 3H, J=7.4 Hz), 1.50-1.59 (m, 2H), 2.51 (s, 3H), 3.00 (s, 3H), 3.73 (t, 2H, J=7.4 Hz), 5.32 (s, 1H), 7.67-7.74 (m, 2H), 8.04 (s, 1H), 8.17 (s, 1H), 8.23 (d, 1H, J=7.6 Hz)
    • Reference Examples 55-57
  • Figure US20140179670A1-20140626-C00157
    • Step 1 Reference Example 55
  • 1-Methyl-3-(3-(trifluoromethyl)phenyl)urea (available from Crescent Chemical Co., Inc.) (4.03 g) and malonic acid (2.11 g) were suspended into acetic anhydride (12 ml) and the resulting mixture was stirred at 80° C. for one hour. After the reaction solutions were concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution and the resulting mixture was washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-methyl-3-(3-(trifluoromethyl)phenyl)pyrimidin-2,4,6-(1H, 3H, 5H)-trione (2.75 g).
  • 1H-NMR (400 MHz, DMSO-d6) (δ PPM):
  • 3.15 (s, 3H), 3.88 (s, 2H), 7.57 (d, 1H, J=7.9 Hz), 7.66 (s, 1H), 7.74 (t, 1H, J=7.9 Hz), 7.82 (d, 1H, J=7.9 Hz)
    • Step 2 Reference Example 56
  • To a solution of 1-methyl-3-(3-(trifluoromethyl)phenyl)pyrimidin-2,4,6(1H, 3H, 5H)-trione (2.74 g) (prepared in Reference Example 55) in phosphorus oxychloride (22 ml) was added water (0.55 ml) slowly and the resulting mixture was stirred with heating under reflux for one hour. After concentration under reduced pressure, the reaction solutions were cooled to 0° C. and to the residue was added water (50 ml) slowly with stirring. The resulting mixture was extracted with ethyl acetate (50 ml×3), and the resulting extracts were dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (1.54 g)
  • 1H-NMR (400 MHz, DMSO-d6) (δ PPM):
  • 3.18 (s, 3H), 6.29 (s, 1H), 7.76-7.83 (m, 2H), 7.89 (d, 1H, J=7.2 Hz), 7.99 (s, 1H)
    • Step 3 Reference Example 57
  • To a solution of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (1.12 g) in THF (tetrahydrofuran) (30 ml) were added under nitrogen atmosphere bis(tri-tert-butyl phosphine)palladium (188 mg) and zinc diethyl (1.1 M hexane solution, 10 ml) and the resulting mixture was stirred at room temperature for twenty minutes. The reaction solutions were added into 1 N (normality) of hydrochloric acid and the resulting mixture was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-ethyl-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (0.94 g).
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.08 (t, 3H, J=7.3 Hz), 2.06 (q, 2H, J=7.3 Hz), 3.37 (s, 3H), 5.79 (s, 1H), 7.45 (d, 1H, J=8.1 Hz), 7.53 (s, 1H), 7.67 (t, 1H, J=7.9 Hz), 7.82 (d, 1H, J=7.9 Hz)
    • Reference Example 58
  • Figure US20140179670A1-20140626-C00158
  • To a mixed solution of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (149 mg) in THF (5 ml) and N-methylpyrrolidone (0.5 ml) were added under nitrogen atmosphere iron(III) acetylacetonate (26 mg) and isopropylmagnesium chloride (2M THF solution, 1 ml), and the resulting mixture was stirred at room temperature for two and a half hours. The reaction solutions were added to 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-isopropyl-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (53 mg).
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.07 (d, 3H, J=6.7 Hz), 1.09 (d, 3H, J=6.7 Hz), 2.30 (sept, 1H, J=6.7 Hz), 3.36 (s, 3H), 5.81 (s, 1H), 7.46 (d, 1H, J=7.9 Hz), 7.53 (s, 1H), 7.68 (t, 1H, J=7.9 Hz), 7.77 (d, 1H, J=7.9 Hz)
    • Reference Example 59
  • Figure US20140179670A1-20140626-C00159
  • To a suspension of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (301 mg) in isopropyl alcohol (10 ml) was added 50% aqueous dimethyl amine solution (0.5 ml) and the resulting mixture was stirred at 80° C. for two and a half hours. The reaction solutions were concentrated under reduced pressure, and to the residue were added water and methanol, and the resulting mixture was stirred. The precipitated solids were collected by filtration, and washed with water and diethylther to afford 6-(dimethylamino)-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (220 mg).
  • 1H-NMR (400 MHz, DMSO-d6) (δ PPM):
  • 2.41 (s, 6H), 3.13 (s, 3H), 5.22 (s, 1H), 7.68-7.71 (m, 2H), 7.76-7.79 (m, 1H), 7.85 (s, 1H)
    • Reference Examples 60-61
  • Figure US20140179670A1-20140626-C00160
    • Step 1 Reference Example 60
  • To a solution of 3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 20) (800.0 mg) in acetic acid (13.0 ml) was added in water bath N-iodosuccinimide (784.5 mg) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was added water (20 ml) and the resulting mixture was stirred for thirty minutes, and thereto was added sodium thiosulfate solution (20 ml) and the resulting mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with water to afford 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (819.3 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.22 (s, 3H), 3.43 (s, 3H), 7.43 (d, 1H, J=7.8 Hz), 7.49 (s, 1H), 7.67 (t, 1H, J=7.8 Hz), 7.77 (d, 1H, J=8.1 Hz)
    • Step 2 Reference Example 61
  • A solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (20.0 mg), propargylaldehyde diethyl acetal (62.5 mg), tetrakis(triphenylphosphine)palladium (5.6 mg), copper iodide (1.0 mg) and triethylamine (68 μL) in tetrahydrofuran (1.0 ml) was stirred at room temperature under nitrogen atmosphere for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (216.0 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.23 (t, 6H, J=7.2 Hz), 2.09 (s, 3H), 3.37 (s, 3H), 3.60-3.66 (m, 2H), 3.75-3.81 (m, 2H), 5.48 (s, 1H), 7.42 (d, 1H, J=7.2 Hz), 7.49 (s, 1H), 7.67 (t, 1H, J=8.1 Hz), 7.78 (d, 1H, J=7.8 Hz)
    • Reference Examples 62-92
  • The below-mentioned compounds Ic (Reference Examples 62-92) were obtained by using the compounds of Reference Examples 21-51 according to the similar reaction and treatment method to those described in Reference Example 60.
  • Figure US20140179670A1-20140626-C00161
  • TABLE 7
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    62
    Figure US20140179670A1-20140626-C00162
    Figure US20140179670A1-20140626-C00163
         		1 0.86 (t, 3H, J = 7.4 Hz), 1.52-1.60 (m, 2H), 2.11 (d, 3H, J = 1.2 Hz), 3.81 (t, 2H, J = 7.4 Hz), 7.76-7.80 (m, 2H), 7.84-7.90 (m, 1H), 7.96 (s, 1H)
    63
    Figure US20140179670A1-20140626-C00164
    Figure US20140179670A1-20140626-C00165
         		1 1.24 (3H, t, J = 6.9 Hz), 2.24 (3H, s), 4.22 (2H, t, J = 7.2 Hz), 4.74 (2H, s), 7.45 (d, 1H, J = 7.8 Hz), 7.52 (s, 1H), 7.66 (t, 1H, J = 8.1 Hz), 7.76 (t, 1H, J = 7.8 Hz)
    64
    Figure US20140179670A1-20140626-C00166
    Figure US20140179670A1-20140626-C00167
         		1 1.21 (t, 3H, J = 7.2 Hz), 2.22 (s, 3H), 2.66 (t, 2H, J = 7.5H), 4.11 (q, 2H, J = 7.8 Hz), 4.31 (t, 2H, J = 7.2 Hz), 7.43 (d, 1H, J = 8.1 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 8.1 Hz), 7.76 (d, 1H, J = 8.1 Hz)
    65
    Figure US20140179670A1-20140626-C00168
    Figure US20140179670A1-20140626-C00169
         		1 1.21 (t, 3H, J = 7.2 Hz), 1.99 (quin, 2H, J = 7.2 Hz), 2.21 (s, 3H), 2.35 (t, 2H, J = 7.8 Hz), 4.08 (q, 4H, J = 7.2 Hz), 7.44 (d, 1H, J = 7.2 Hz), 7.50 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 8.1 Hz)
    66
    Figure US20140179670A1-20140626-C00170
    Figure US20140179670A1-20140626-C00171
         		1 2.26 (s, 3H), 4.82 (s, 2H), 5.19 (s, 2H), 7.31-7.37 (m, 5H), 7.43 (d, 1H, J = 7.8 Hz), 7.52 (s, 1H), 7.68 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 7.8 Hz)
    67
    Figure US20140179670A1-20140626-C00172
    Figure US20140179670A1-20140626-C00173
         		1 2.22 (s, 3H), 3.34 (s, 6H), 4.16 (d, 2H, J = 5.8 Hz), 4.83 (t, 1H, J = 5.8 Hz), 7.43 (d, 1H, J = 7.9 Hz), 7.50 (s, 1H), 7.66 (t, 1H, J = 7.9 Hz), 7.75 (d, 1H, J = 7.9 Hz)
  • TABLE 8
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    68
    Figure US20140179670A1-20140626-C00174
    Figure US20140179670A1-20140626-C00175
         		1 1.30-1.36 (m, 2H), 1.41 (s, 9H), 1.44-1.50 (m, 2H), 1.62-1.68 (m, 2H), 2.21 (s, 3H), 3.02-3.12 (m, 2H), 3.98 (t, 2H, J = 7.7 Hz), 4.50 (brs, 1H), 7.42 (d, 1H, J = 8.4 Hz), 7.50 (s, 1H), 7.66 (t, 1H, J = 8.4 Hz), 7.75 (d, 1H, J = 8.4 Hz)
    69
    Figure US20140179670A1-20140626-C00176
    Figure US20140179670A1-20140626-C00177
         		1 2.18 (s, 2H), 2.19 (s, 1H), 3.75 (s, 2H), 3.82 (s, 1H), 5.05 (s, 0.5H), 5.10 (s, 1.5H), 6.72 (d, 0.5H, J = 8.4 Hz), 6.81 (d, 1.5H, J = 8.7 Hz), 7.38 -7.51 (m, 4H), 7.62-7.74 (m, 2H)
    70
    Figure US20140179670A1-20140626-C00178
    Figure US20140179670A1-20140626-C00179
         		4 2.26 (s, 3H), 3.46 (s, 3H), 7.52 (ddd, 1H, J = 1.3, 1.6, 7.9 Hz), 7.58 (t, 1H. J = 1.6 Hz), 7.70 (t, 1H, J = 7.9 Hz), 7.83 (dt, 1H, J = 1.3, 7.9 Hz)
    71
    Figure US20140179670A1-20140626-C00180
    Figure US20140179670A1-20140626-C00181
         		4 2.18 (s, 3H), 3.38 (s, 3H), 3.87 (s, 3H), 7.35 (ddd, 1H, J = 1.3, 1.8, 7.9 Hz), 7, 56 (t, 1H, J = 7.9 Hz), 7.83 (t, 1H, J = 1.8 Hz), 8.10 (dt, 1H, J = 1.3, 7.9 Hz)
    72
    Figure US20140179670A1-20140626-C00182
    Figure US20140179670A1-20140626-C00183
         		4 2.20 (s, 3H), 3.38 (s, 3H), 6.91 (dt, 1 H, J = 2.2, 8.6 Hz), 6.96 (dd, 1H, J = 1.2, 7.9 Hz), 7.13-7.20 (m, 1H), 7.45 (dt, 1H, J = 6.1, 8.2 Hz)
    73
    Figure US20140179670A1-20140626-C00184
    Figure US20140179670A1-20140626-C00185
         		4 2.21 (s, 3H), 3.38 (s, 3H), 3.76 (s, 3H), 6.66 (dd, 1H, J = 1.9, 2.2 Hz), 6.72 (ddd, 1H, J = 0.8, 1.9, 8.0 Hz), 6.95 (ddd, 1 H, J = 0.8, 2.2, 8.0 Hz), 7.36 (t, 1H. J = 8. 1 Hz)
    74
    Figure US20140179670A1-20140626-C00186
    Figure US20140179670A1-20140626-C00187
         		4 2.19 (s, 3H), 3.38 (s, 3H), 7.32 (t, 1H, J = 8.9 Hz), 7.34-7.39 (m, 1H), 7.42-7.45 (m, 1H)
    75
    Figure US20140179670A1-20140626-C00188
    Figure US20140179670A1-20140626-C00189
         		1 2.17 (s, 3H), 3.42 (s, 3H), 7.33 (d, 1H, J = 7.5 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.74 (t, 1H, J = 7.8 Hz), 7.85 (d, 1H, J = 7.8 Hz)
  • TABLE 9
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    76
    Figure US20140179670A1-20140626-C00190
    Figure US20140179670A1-20140626-C00191
         		1 2.21 (s, 1H), 2.22 (s, 2H), 3.42 (s, 1H), 3.43 (s, 2H), 7.37 (d, 2H, J = 8.1 Hz), 7.81 (d, 2H, J = 7.8 Hz)
    77
    Figure US20140179670A1-20140626-C00192
    Figure US20140179670A1-20140626-C00193
         		1 2.18 (s, 3H), 3.37 (s, 3H), 7.56 (d, 1H, J = 7.8 Hz), 7.79 (d, 1H, J = 7.8 Hz), 8.08 (t, 1H, J = 7.8 Hz)
    78
    Figure US20140179670A1-20140626-C00194
    Figure US20140179670A1-20140626-C00195
         		1 2.24 (s, 3H), 3.42 (s, 3H), 7.14-7.17 (m, 1H), 7.37-7.42 (m, 2H), 7.60-7.63 (m, 1H)
    79
    Figure US20140179670A1-20140626-C00196
    Figure US20140179670A1-20140626-C00197
         		1 2.24 (s, 3H), 3.42 (s, 3H), 7.09-7.13 (m, 1H), 7.22-7.23 (m, 1H), 7.45-7.47 (m, 2H)
    80
    Figure US20140179670A1-20140626-C00198
    Figure US20140179670A1-20140626-C00199
         		1 2.25 (s, 3H), 3.43 (s, 3H), 7.55-7.59 (m, 1H), 7.74 (t, 1H, J = 8.2 Hz), 8.12 (t, 1H, J = 2.1 Hz), 8.35-8.38 (m, 1H)
    81
    Figure US20140179670A1-20140626-C00200
    Figure US20140179670A1-20140626-C00201
         		1 2.23 (s, 3H), 2.39 (s, 3H), 3.43 (s, 3H), 6.97-6.99 (m, 2H), 7.27 (d, 1H, J = 7.2 Hz), 7.39 (t, 1H, J = 6.6 Hz)
    82
    Figure US20140179670A1-20140626-C00202
    Figure US20140179670A1-20140626-C00203
         		1 1.31 (s, 9H), 2.21 (s, 3H) 3.43 (s, 3H), 6.97-7.00 (m, 1H), 7.14-7.16 (m, 1H), 7.40-7.50 (m, 2H)
    83
    Figure US20140179670A1-20140626-C00204
    Figure US20140179670A1-20140626-C00205
         		1 2.22 (s, 3H), 3.10 (s, 3H), 3.43 (s, 3H), 7.05-7.36 (m, 1H), 7.76 (t, 1H, J = 7.8 Hz), 7.82 (t, 1H, J = 1.5 Hz), 8.04-8.08 (m, 1H)
    84
    Figure US20140179670A1-20140626-C00206
         		Et 1 1.24 (t, 3H, J = 7.2 Hz), 2.21 (s, 3H), 4.06 (q, 2H, J = 7.2 Hz), 7.42 (d. 1H, J = 8.1 Hz), 7.50 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 8.1 Hz)
    85
    Figure US20140179670A1-20140626-C00207
         		1Pr 1 1.45 (d, 6H, J = 6.9 Hz), 2.18 (s, 3H), 5.19 (quintet, 1H. J = 7.8 Hz). 7.42 (d, 1H, J = 7.8 Hz), 7.50 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.74 (d, 1H, J = 8.4 Hz)
  • TABLE 10
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    86
    Figure US20140179670A1-20140626-C00208
         		cPr 1 0.79-0.85 (in, 2H), 1.12 (q, 2H, J = 6.9 Hz), 2.19 (s, 3H), 2.72-2.82 (m, 1H), 7.40 (d, 1H, J = 7.8 Hz), 7.48 (s, 1H), 7.65 (t, 1H, J = 7.8 Hz), 7.73 (d, 1H, J = 7.8 Hz)
    87
    Figure US20140179670A1-20140626-C00209
    Figure US20140179670A1-20140626-C00210
         		1 1.63-1.91 (m, 2H), 2.16-2.28 (m, 5H), 2.86 (dseptet, 2H, J = 9.6, 2.4 Hz), 5.24 (septet, 1H, J = 8.7 Hz), 7.42 (d, 1H, J = 7.8 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.74 (d, 1H. J = 7.8 Hz)
    88
    Figure US20140179670A1-20140626-C00211
    Figure US20140179670A1-20140626-C00212
         		1 2.22 (s, 3H), 4.25 (t, 2H, J = 9.0 Hz), 4.47 (dd, 2H, J = 9.0, 7.2 Hz), 5.07 (s, 2H), 5.37-5.42 (m, 1H), 7.27-7.33 (n, 5H), 7.41 (d, 1H, J = 7.8 Hz), 7.48 (s, 1H), 7.68 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 8.1 Hz)
    89
    Figure US20140179670A1-20140626-C00213
    Figure US20140179670A1-20140626-C00214
         		1 1.22 (dt, 3H, J = 6.9, 0.9 Hz), 1.58 (d, 3H, J = 6.9 Hz), 2.23 (s, 3H), 4.10-4.25 (m, 2H), 5.50 (dq, 1H, J = 6.9, 1.8 Hz), 7.40-7.53 (m, 2H), 7.66 (t, 1H, J = 7.5 Hz), 7.75 (d, 1H, J = 7.8 Hz)
    90
    Figure US20140179670A1-20140626-C00215
    Figure US20140179670A1-20140626-C00216
         		1 1.46 (d, 3H, J = 6.9 Hz), 2.00 (s, 3H), 2.21 (s, 3H), 4.29-4.38 On, 1H), 4.57-4.68 (m, 1H), 5.25 (brs, 1H), 7.42 (t, 1H, J = 9.3 Hz), 7.51 (d, 1H, J = 15.6 Hz), 7.67 (t, 1H, J = 6.9 Hz), 7.75 (d, 1H. J = 7.8 Hz)
    91
    Figure US20140179670A1-20140626-C00217
    Figure US20140179670A1-20140626-C00218
         		4 1.75 (d, 1.5H, J = 7.1 Hz), 1.76 (d, 1.5H, J = 7.0 Hz), 2.11 (s, 3H), 6.10 (q, 1H, J = 6.9 Hz), 7.20-7.24 (n. 1H), 7.28-7.34 (m, 4H), 7.72-7.79 (m, 1.5H), 7.82-7.87 (m, 1.5 Hz), 7.94 (s, 0.5H), 8.03 (s, 0.5H)
    92
    Figure US20140179670A1-20140626-C00219
    Figure US20140179670A1-20140626-C00220
         		1 1.98 (s, 3H), 2.22 (s, 3H), 4.30-4.35 (m, 4H), 7.43 (d, 1H, J = 7.8 Hz), 7.50 (s, 1H), 7.67 (t, 1H, J = 8.1 Hz), 7.75 (d, 1H, J = 7.8 Hz)
    • Reference Examples 93-94
  • The compounds Id (Reference Examples 93-94) indicated in the below-mentioned Table were obtained by using the compounds of Reference Examples 53-54 according to the similar reaction and treatment method to those described in Reference Example 60.
  • Figure US20140179670A1-20140626-C00221
  • TABLE 11
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    93
    Figure US20140179670A1-20140626-C00222
    Figure US20140179670A1-20140626-C00223
         		1 2.60 (s, 3H), 2.98 (s, 3H), 3.42 (s, 3H), 7.35 (d, 1H, J = 7.8 Hz), 7.42 (s, 1H), 7.52 (t, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.64 (s, 1H)
    94
    Figure US20140179670A1-20140626-C00224
    Figure US20140179670A1-20140626-C00225
         		1 0.87 (t, 3H, J = 7.4 Hz), 1.51-1.61 (m, 2H), 2.51 (s, 3H), 2.94 (s, 3H), 3.81 (t, 2H, J = 7.4 Hz), 7.68- 7.74 (m, 2H), 7.82 (s, 1H), 8.21-8.23 (m, 2H)
    • Reference Examples 95-98
  • Figure US20140179670A1-20140626-C00226
    • Step 1 Reference Example 95
  • To an aqueous solution of 3-trifluoromethylphenyl aniline (5.0 g) in water (15.0 ml) was added acrylic acid (3.2 ml) and the resulting mixture was stirred at 100° C. for one hour. The reaction mixture was basified with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate (100 ml×2). The resulting organic layer was washed with saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(3-trifluoromethylphenylamino)propionic acid (8.4 g).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.68 (t, 2H, J=6.0 Hz), 3.48 (t, 2H, J=6.2 Hz), 6.74 (d, 1H, J=8.0 Hz), 6.80 (s, 1H), 6.94 (d, 1H, J=7.5 Hz), 7.22-7.27 (m, 1H)
    • Step 2 Reference Example 96
  • A solution of 3-(3-trifluoromethylphenylamino)propanoic acid (2.0 g) (prepared in Reference Example 95) and urea (1.0 g) in acetic acid (20.0 ml) was stirred with heating under reflux for seven hours. To the reaction mixture was water (50 ml) and the resulting mixture was extracted with ethyl acetate (30 ml×3). The organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (1.5 g).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.86 (t, 2H, J=6.6 Hz), 3.91 (t, 2H, J=6.7 Hz), 7.50-7.54 (m, 4H), 7.80 (brs, 1H)
    • Step 3 Reference Examples 97 and 98
  • To a solution of 1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 96) (770.0 mg) in acetic acid (10.0 ml) was added bromine (0.18 ml) and the resulting mixture was stirred with heating under reflux for two hours. To the reaction mixture were added water (30 ml) and 10% aqueous sodium thiosulfate solution (5 ml) and the precipitated solids were collected by filtration with water to afford a mixture containing 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione, 5,5-dibromo-1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione and 5-bromo-1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (800.0 mg). A solution of the resulting mixture (800.0 mg) and lithium chloride (122.3 mg) in N,N-dimethyl formamide (5.0 ml) was stirred at 120° C. for one and a half hours. To the reaction mixture was added water (20 ml) and the resulting mixture was extracted with ethyl acetate (20 ml×2), and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (473.1 mg) and 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (135.8 mg).
    • 5-Bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (Reference Example 97)
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 7.52 (d, 1H, J=8.3 Hz), 7.58 (s, 1H), 7.60-7.63 (m, 2H), 7.68 (d, 1H, J=7.9 Hz), 8.50 (brs, 1H)
    • 1-(3-Trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (Reference Example 98)
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 5.83 (d, 1H, J=7.9 Hz), 7.29 (d, 1H, J=6.8 Hz), 7.50-7.66 (m, 4H), 9.27 (brs, 1H)
    • Reference Example 99
  • Figure US20140179670A1-20140626-C00227
  • To a solution of uracil (8.9 g), copper(II) acetate (9.6 g), N,N,N,N-tetramethylethylenediamine (10.2 ml) in methanol/dimethy formamide/water (500/100/100 ml) was added 3-trifluoromethylphenyl boronic acid (10.0 g) and the resulting mixture was stirred at room temperature for twelve hours. The reaction mixture was concentrated under reduced pressure so as to remove methanol and thereto was added water (100 ml). The resulting mixture was extracted with ethyl acetate (100 ml×3) and the organic layer was washed with water (100 ml×2) and saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (650.0 mg).
    • Reference Example 100
  • Figure US20140179670A1-20140626-C00228
  • To a solution of 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 98 or 99) (135.0 mg) in N,N-dimethy formamide (5.0 ml) were added at room temperature sodium hydride (25.3 mg) and isopropyl iodide (265 μl) and the resulting mixture was stirred at 110° C. for two hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (30.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 3-isopropyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (122.5 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.43 (d, 6H, J=7.00 Hz), 5.12-5.22 (m, 1H), 7.79 (d, 1H, J=7.9 Hz), 7.17 (d, 1H, J=7.9 Hz), 7.48-7.64 (m, 4H)
    • Reference Example 101-103
  • Figure US20140179670A1-20140626-C00229
    • Step 1 Reference Example 101
  • To a solution of 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 98 or 99) (740.0 mg) in tetrahydrofuran (10.0 ml) was added (R)-1-(tert-butyldiphenylsilyloxy)propane-2-ol (1.82 g), triphenylphosphine (1.5 g) and diethyl azodicarboxylate (2.7 ml:2.2 M toluene solution) and the resulting mixture was stirred at room temperature for twelve hours. To the reaction mixture was added water (50 ml), and the resulting mixture was extracted with ethyl acetate (30 ml×2) and the organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-3-[1-(tert-butyldiphenylsilyloxy)propane-2-yl]-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (969.8 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 0.98 (s, 9H), 1.36 (d, 3H, J=7.1 Hz), 3.77 (dd, 1H, J=9.9, 5.9 Hz), 4.30 (t, 1H, J=9.5 Hz), 5.26-5.40 (m, 1H), 5.86 (d, 1H, J=7.9 Hz), 7.23 (d, 1H, J=7.9 Hz), 7.33-7.70 (m, 14H)
    • Step 2 Reference Example 102
  • To a solution of (R)-3-[1-(tert-butyldiphenylsilyloxy)propane-2-yl]-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 101) (7.1 g) in ethanol (50.0 ml) was added 1N hydrochloric acid (64.0 ml) and the resulting mixture was stirred at 90° C. for two hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol) to afford (R)-3-(1-hydroxypropan-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (2.6 g).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.45 (d, 3H, J=7.0 Hz), 3.01 (brd, 1H, J=10.8 Hz), 3.83-3.88 (m, 1H), 3.99-4.09 (m, 1H), 5.21-5.27 (m, 1H), 5.90 (d, 1H, J=7.9 Hz), 7.27 (d, 1H, J=7.9 Hz), 7.56 (d, 1H, J=8.1 Hz), 7.60-7.63 (m, 2H), 7.69 (t, 1H, J=8.4 Hz)
    • Step 3 Reference Example 103
  • To a solution of (R)-3-(1-hydroxypropan-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 102) (1.3 g) in chloroform (20.0 ml) was added iodine chloride (12.4 ml, 1M dichloromethane solution) and the resulting mixture was stirred for two hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-3-(1-hydroxypropan-2-yl)-5-iodo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (1.4 g).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.44 (d, 3H, J=7.3 Hz), 3.75-3.80 (m, 1H), 3.88-3.93 (m, 1H), 4.76-4.82 (m, 1H), 7.40 (d, 1H, J=7.2 Hz), 7.49 (s, 1H), 7.60 (t, 1H, J=7.9 Hz), 7.68 (d, 1H, J=7.5 Hz), 7.90 (s, 1H)
    • Reference Example 104
  • Figure US20140179670A1-20140626-C00230
  • To a solution of 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 97) (150.0 mg) and potassium carbonate (181.6 mg) in N,N-dimethy formamide (4.0 ml) was added at room temperature, methyl iodide (0.042 ml) and the resulting mixture was stirred at 70° C. for two and a half hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (20.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-3-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4 (H,3H)-dione (153.6 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 3.41 (s, 3H), 7.50 (d, 1H, J=7.9 Hz), 7.57-7.62 (m, 3H), 7.67 (d, 1H, J=7.7 Hz)
    • Reference Example 105
  • Figure US20140179670A1-20140626-C00231
  • The compound was prepared according to the similar process to those of Reference Example 104.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.38 (s, 9H), 1.52 (d, 3H, J=7.2 Hz), 5.41 (q, 1H, J=7.0 Hz), 5.17-5.26 (m, 1H), 7.50 (d, 1H, J=7.9 Hz), 7.56-7.67 (m, 4H)
    • Reference Examples 106-110
  • The compound 1e indicated in the below-mentioned table (Reference Examples 106-110) was obtained by using the compounds of Reference Examples 57-59 and 99-100 according to the similar reaction and treatment method to those described in Reference Example 60.
  • Figure US20140179670A1-20140626-C00232
  • TABLE 12
    Ref. Measurement
    Ex. Ar1 R1 R4 cond. 1H-NMR (δ PPM)
    106
    Figure US20140179670A1-20140626-C00233
         		Me Et 4 1.03 (t, 3H, J = 7.5 Hz), 2.55 (q, 2H, J = 7.5 Hz), 3.45 (s, 3H), 7.47 (d, 1H, J = 7.9 Hz), 7.55 (s, 1H), 7.70 (t, 1H, J = 7.9 Hz), 7.79 (d, 1H, J = 7.9 Hz)
    107
    Figure US20140179670A1-20140626-C00234
         		Me iPr 4 1.24 (brs, 6H), 2.80 (brs, 1H), 3.44 (s, 3H), 7.44 (d, 1H, J = 7.9 Hz), 7.52 (s, 1H), 7.68 (t, 1H, J = 7.9 Hz), 7.78 (d, 1H, J = 7.9 Hz)
    108
    Figure US20140179670A1-20140626-C00235
         		Me NMe2 4 2.38 (s, 6H), 3.22 (s, 3H), 7.71-7.73 (m, 2H), 7.78-7.80 (m, 1H), 7.86 (s, 1H)
    109
    Figure US20140179670A1-20140626-C00236
         		H H 3 7.58 (d, 1H, J = 8.3 Hz), 7.64 (s, 1H), 7.67 (t, 1H, J = 7.9 Hz), 7.74 (d, 1H, J = 7.8 Hz), 7.80 (s, 1H), 8.31 (s, 1H)
    110
    Figure US20140179670A1-20140626-C00237
         		iPr H 1 1.43 (d, 6H, J = 6.9 Hz), 5.19 (quin, 1H, J = 6.9 Hz), 7.50 (d, 1H, J = 8.1 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 9.9 Hz), 7.67 (s, 1H)
    • Reference Examples 111-114
  • Figure US20140179670A1-20140626-C00238
    • Step 11 Reference Example 111
  • Ethyl 2-cyano-3-ethoxyacryloyl carbamate (prepared by the method described in Chem. Pharm. Bull. 1972, 20, 1380-1388) (20.0 g) was suspended in ethanol (200 ml) and thereto was added 3-(trifluoromethyl)aniline (12.36 ml), and the resulting mixture was stirred at room temperature for nineteen hours. The precipitated solids were collected by filtration and washed with ethanol to afford ethyl 2-cyano-3-(3-(trifluoromethyl)phenylamino)acryloyl carbamate. Further, the filtrates were concentrated and thereto was added ethanol, and the solids were collected by filtration, and washed with ethanol three times repeatedly to afford the intended products (26.2 g).
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.34 (t, 3H, J=6.8 Hz), 4.28 (q, 2H, J=6.9 Hz), 7.38 (d, 1H, J=5.7 Hz), 7.44 (s, 1H), 7.49-7.53 (m, 1H), 7.56-7.58 (m, 1H), 7.78 (s, 1H), 8.26-8.30 (m, 1H), 8.57-8.63 (m, 1H)
    • Step 2 Reference Example 112
  • To a suspension of 2-cyano-3-(3-(trifluoromethyl)phenylamino)acryloylcarbamate (prepared in Reference Example 111) (26.2 g) in acetonitrile (300 ml) was added triethylamine (111 ml) and the resulting mixture was stirred for six hours with heating under reflux. The reaction solutions were concentrated under reduced pressure, and to the residue was added 1M hydrochloric acid and the resulting mixture was extracted with ethyl acetate twice. The organic layer was washed with 1M hydrochloric acid and saturated saline. The resulting mixture was dried over anhydrous magnesium and then concentrated under reduced pressure to afford 2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile (22.7 g).
  • 1H-NMR (400 MHz, DMSO-d6) (δ PPM):
  • 7.75-7.83 (m, 2H), 7.87 (d, 1H, J=7.5 Hz), 7.96 (s, 1H), 8.89 (s, 1H), 12.25 (s, 1H)
    • Step 3 Reference Example 113
  • 2,4-Dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile (prepared in Reference Example 112) (22.7 g) was suspended in hydrobromic acid (48%, 220 ml) and the resulting mixture was stirred with heating under reflux for ten hours. The resulting mixture was cooled to 0° C. and to the reaction solutions was then added 28% ammonia water (145 ml) dropwise, and the precipitated solids were collected by filtration and washed with water to afford 1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (17.8 g).
    • Step 4 Reference Example 114
  • To a suspension of 1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 113) (5.09 g) in acetonitrile (75 ml) were added iodine (3.03 g) and cerium ammonium nitrate (6.54 g) and the resulting mixture was stirred at 80° C. for thirty minutes. The resulting mixture was cooled to 0° C. and thereto were then added ethyl acetate (150 ml), saturated saline (50 ml) and 5% sodium hydrogen sulfite solution (100 ml) so as to separate the layer. Furthermore, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen sulfite solution and saturated saline. The resulting mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue were added ethyl acetate (50 ml) and hexane (100 ml) and the resulting mixture was stirred for fifteen minutes, and the precipitated solids were then collected by filtration and washed with hexane to afford 5-iodo-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (7.34 g).
    • Reference Examples 115-119
  • Figure US20140179670A1-20140626-C00239
    • Step 1 Reference Example 115
  • The intended product, (Z)-ethyl 2-cyano-3-(2-methyl-5-(trifluoromethyl)phenylamino)acryloylcarbamate was obtained according to the similar process to those of Reference Example 111.
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.35 (t, 3H, J=7.1 Hz), 2.46 (s, 3H), 4.29 (q, 2H, J=7.1 Hz), 7.36-7.43 (m, 3H), 7.91 (s, 1H), 7.93 (d, 1H, J=13.0 Hz), 11.76 (d, 1H, J=12.6 Hz)
    • Step 2 Reference Example 116
  • The intended product, 1-(2-methyl-5-(trifluoromethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carbonitrile was obtained according to the similar process to those of Reference Example 112.
  • 1H-NMR (400 MHz, DMSO-d6) (δ PPM):
  • 2.25 (s, 3H), 7.64 (d, 1H, J=8.1 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.92 (s, 1H), 8.78 (s, 1H), 12.27 (s, 1H)
    • Step 3 Reference Example 117
  • The intended product, 1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione was obtained according to the similar process to those of Reference Example 113.
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 2.32 (s, 3H), 5.87 (dd, 1H, J=1.2, 7.9 Hz), 7.18 (d, 1H, J=7.9 Hz), 7.48-7.52 (m, 2H), 7.65 (dd, 1H, J=1.1, 8.1 Hz), 8.57 (s, 1H)
    • Step 4 Reference Example 118
  • The intended product, 5-iodo-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione was obtained according to the similar process to those of Reference Example 114.
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 2.33 (s, 3H), 7.48-7.52 (m, 2H), 7.65 (s, 1H), 7.67 (d, 1H, J=8.1 Hz), 8.46 (s, 1H)
    • Step 5 Reference Example 119
  • To a solution of 5-iodo-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 118) (645 mg) in THF (20 ml) were added isopropyl alcohol (0.25 ml), triphenylphosphine (855 mg), diethyl azodicarboxylate (2.2 M toluene solution, 1.48 ml), and the resulting mixture was stirred at room temperature for twenty-five minutes. The reaction solutions were concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-iodo-3-isopropyl-1-(2-methyl-5-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (548 mg).
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.49-1.56 (m, 6H), 2.28 (s, 3H), 5.24-5.29 (m, 1H), 7.48-7.50 (m, 2H), 7.60 (s, 1H), 7.64 (d, 1H, J=7.8 Hz)
    • Reference Examples 120-151
  • The compounds If indicated in the below-mentioned Table (Reference Examples 120-151) were obtained by using the compounds of Reference Examples 62-92 or known compounds according to the similar reaction and treatment method to those described in Reference Example 61.
  • Figure US20140179670A1-20140626-C00240
  • TABLE 13
    Ref. Measurement 1H-NMR (δ PPM)
    Ex. Ar1 R1 cond. (or LC-MS: [M + H]+/Rt)
    120
    Figure US20140179670A1-20140626-C00241
    Figure US20140179670A1-20140626-C00242
         		1 0.87 (t, 3H, J = 7.4 Hz), 1.16 (t, 6H, J = 7.5 Hz), 1.57- 1.65 (m, 2H), 2.04 (s, 3H), 3.56 (q, 1H, J = 7.5 Hz), 3.60 (q, 1H, J = 7.5 Hz), 3.68-3.78 (m, 2H), 3.85 (t, 2H, J = 7.4 Hz), 5.43 (s, 1H), 7.35 (d, 1H, J = 7.9 Hz), 7.44 (s, 1H), 7.62 (t, 1H, J = 7.9 Hz), 7.71 (d, 1H, J = 7.9 Hz)
    121
    Figure US20140179670A1-20140626-C00243
    Figure US20140179670A1-20140626-C00244
         		1 437 (M—OEt)/2.43 (min)
    122
    Figure US20140179670A1-20140626-C00245
    Figure US20140179670A1-20140626-C00246
         		1 1.19-1.25 (m 9H), 2.09 (s, 3H), 2.65 (t, 2H, J = 7.5 Hz), 3.58-3.68 (m, 2H), 3.73-3.82 (m, 2H), 4.10 (q, 2H, J = 7.2 Hz), 4.25 (t, 2H, J = 7.2 Hz), 5.47 (s, 1H), 7.42 (d, 1H, J = 6.9 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 7.8 Hz)
    123
    Figure US20140179670A1-20140626-C00247
    Figure US20140179670A1-20140626-C00248
         		1 1.15-1.29 (m, 9H), 2.04 (s, 3H), 2.31 (t, 2H, J = 7.2 Hz), 3.49-3.63 (m, 2H), 3.68-3.78 (m, 2H), 4.10 (q, 2H, J = 7.2 Hz), 4.25 (t, 2H, J = 7.2 Hz), 5.47 (s, 1H), 7.40 (t, 1H, J = 7.5 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 7.8 Hz)
    124
    Figure US20140179670A1-20140626-C00249
    Figure US20140179670A1-20140626-C00250
         		1 1.25 (t, 6H, J = 7.2 Hz), 2.13 (s, 3H), 3.63 (q, 1H, J = 7.2 Hz), 3.66 (q, 1H, J = 7.2 Hz), 3.75-3.84 (m, 2H), 4.77 (s, 2H), 5.19 (s, 2H), 5.49 (s, 1H), 7.32-7.38 (m, 5H), 7.42 (d, 1H, J = 7.9 Hz), 7.51 (s, 1H), 7.68 (t, 1H, J = 7.9 Hz), 7.78 (d, 1H, J = 7.9 Hz)
    125
    Figure US20140179670A1-20140626-C00251
    Figure US20140179670A1-20140626-C00252
         		1 1.22 (t, 6H, J = 7.1 Hz), 2.09 (s, 3H), 3.33 (s, 6H), 3.60 (q, 1H, J = 7.1 Hz), 3.63 (q, 1H, J = 7.1 Hz), 3.71-3.82 (m, 2H), 4.10 (d, 2H, J = 5.7 Hz), 4.81 (t, 1H, J = 5.7 Hz), 5.47 (s, 1H), 7.42 (d, 1H, J = 7.9 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.9 Hz), 7.75 (d, 1H, J = 7.9 Hz)
  • TABLE 14
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    126
    Figure US20140179670A1-20140626-C00253
    Figure US20140179670A1-20140626-C00254
         		1 1.22 (t, 6H, J = 7.1 Hz), 1.32-1.36 (m, 2H), 1.40 (s, 9H), 1.42-1.50 (m, 2H), 1.62-1.68 (m, 2H), 2.08 (s, 3H), 3.02-3.10 (m, 2H), 3.60 (q, 1H, J = 7.1 Hz), 3.64 (q, 1H, J = 7.1 Hz), 3.76 (q, 2H, J = 7.1 Hz), 3.93 (t, 2H, J = 7.5 Hz), 5.47 (s, 1H), 7.42 (d, 1H, J = 7.9 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.9 Hz), 7.75 (d, 1H, J = 7.9 Hz)
    127
    Figure US20140179670A1-20140626-C00255
    Figure US20140179670A1-20140626-C00256
         		1 1.15-1.22 (m, 6H), 2.01 (s, 1.5H), 2.15 (s, 1.5H), 3.52-3.64 (m, 2H), 3.66-3.81 (m, 2H), 3.71 (s, 2H), 3.77 (s, 1H), 5.42 (s, 0.5H), 5.45 (s, 0.5H), 6.72 (d, 0.5H, J = 8.7 Hz), 6.76 (d, 1.5H, J = 8.4 Hz), 7.32- 7.44 (m, 4H), 7.57-7.62 (m, 1H), 7.68 (s, 0.5H), 7.71 (s, 0.5H)
    128
    Figure US20140179670A1-20140626-C00257
    Figure US20140179670A1-20140626-C00258
         		4 1.18 (t, 6H, J = 7.1 Hz), 2.05 (s, 3H), 3.32 (s, 3H), 3.55- 3.62 (m, 2H), 3.68-3.76 (m, 2H), 5.43 (s, 1H), 7.41 (ddd, 1H, J = 1.3, 1.7, 7.9 Hz), 7.49 (t, 1H, J = 1.7 Hz), 7.62 (t, 1H, J = 7.9 Hz), 7.75 (dt, 1H, J = 1.3, 7.9 Hz)
    129
    Figure US20140179670A1-20140626-C00259
    Figure US20140179670A1-20140626-C00260
         		1 1.30 (t, 6H, J = 6.9 Hz), 2.09 (s, 3H), 3.37 (s, 3H), 3.58- 3.68 (m, 2H), 3.73-3.81 (m, 2H), 3.92 (s, 3H), 5.48 (s, 1H), 7.37 (m, 1H), 7.61 (t, 1H, J = 8.1 Hz), 7.88 (t, 1H, J = 2.1 Hz), 8.17 (dt, 1H, J = 7.8, 1.2 Hz)
    130
    Figure US20140179670A1-20140626-C00261
    Figure US20140179670A1-20140626-C00262
         		1 1.23 (t, 6H, J = 6.9 Hz), 2.12 (s, 3H), 3.36 (s, 3H), 3.60- 3.66 (m, 2H), 3.76-3.81 (m, 2H), 5.48 (s, 1H), 6.93- 7.01 (m, 2H), 7.19-7.22 (m, 1H), 7.46-7.53 (m, 1H)
  • TABLE 15
    Ref. Measurement 1H-NMR (δ PPM)
    Ex. Ar1 R1 cond. (or LC-MS: [M + H]+/Rt)
    131
    Figure US20140179670A1-20140626-C00263
    Figure US20140179670A1-20140626-C00264
         		4 1.18 (t, 6H, J = 7.1 Hz), 2.08 (s, 3H), 3.31 (s, 3H), 3.55- 3.62 (m, 2H), 3.70-3.78 (m, 2H), 3.76 (s, 3H), 5.43 (s, 1H), 6.65 (t, 1H, J = 2.2 Hz), 6.70-6.73 (m, 1H), 6.95- 6.97 (m, 1H), 7.36 (t, 1H, J = 8.1 Hz)
    132
    Figure US20140179670A1-20140626-C00265
    Figure US20140179670A1-20140626-C00266
         		4 1.18 (t, 6H, J = 7.1 Hz), 2.06 (s, 3H), 3.31 (s, 3H), 3.55- 3.62 (m, 2H), 3.69-3.77 (m, 2H), 5.43 (s, 1H), 7.28- 7.47 (m, 3H)
    133
    Figure US20140179670A1-20140626-C00267
    Figure US20140179670A1-20140626-C00268
         		4 1.27 (t, 6H, J = 7.1 Hz), 2.13 (s, 3H), 3.41 (s, 3H), 3.63- 3.71 (m, 2H), 3.77-3.87 (m, 2H), 5.52 (s, 1H), 7.18- 7.29 (m, 2H), 7.47-7.58 (m, 3H)
    134
    Figure US20140179670A1-20140626-C00269
    Figure US20140179670A1-20140626-C00270
         		8 365 (M—OEt)/2.29 (min)
    135
    Figure US20140179670A1-20140626-C00271
    Figure US20140179670A1-20140626-C00272
         		1 1.23 (t, 6H, J = 6.9 Hz), 2.10 (s, 3H), 3.67 (s, 3H), 3.58- 3.68 (m, 2H), 3.74-3.84 (m, 2H), 5, 48 (s, 1H), 7.36 (d, 2H, J = 8.4 Hz), 7.81 (d, 2H, J = 8.4 Hz)
    136
    Figure US20140179670A1-20140626-C00273
    Figure US20140179670A1-20140626-C00274
         		8 366 (M—OEt)/2.25 (min)
    137
    Figure US20140179670A1-20140626-C00275
    Figure US20140179670A1-20140626-C00276
         		1 1.23 (t, 6H, J = 6.9 Hz), 2.11 (s, 3H), 3.36 (s, 3H), 3.58- 3.68 (m, 2H), 3.73-3.81 (m, 2H), 5.48 (s, 1H), 7.08- 7.11 (m, 1H), 7.21-7.24 (m, 1H), 7.45-7.48 (m, 2H)
    138
    Figure US20140179670A1-20140626-C00277
    Figure US20140179670A1-20140626-C00278
         		1 1.28 (t, 6H, J = 7.2 Hz), 2.11 (s, 3H), 3.36 (s, 3H), 3.58- 3.68 (m, 2H), 3.73-3.83 (m, 2H), 5.47 (s, 1H), 7.13- 7.16 (m, 1H), 7.37-7.46 (m, 2H), 7.61-7.64 (m, 1H)
  • TABLE 16
    Ref. Measurement 1H-NMR (δ PPM)
    Ex. Ar1 R1 cond. (or LC-MS: [M + H]+/Rt)
    139
    Figure US20140179670A1-20140626-C00279
    Figure US20140179670A1-20140626-C00280
         		1 1.23 (t, 6H, J = 7.1 Hz), 2.12 (s, 3H), 3.37 (s, 3H), 3.60 (q, 1H, J = 7.1 Hz), 3.64 (q, 1H, J = 7.1 Hz), 3.73-3.82 (m, 2H), 7.54-7.58 (m, 1H), 7.74 (t, 1H, J = 8.1 Hz), 8.12 (t, 1H, J = 2.0 Hz), 8.35-8.39 (m, 1H)
    140
    Figure US20140179670A1-20140626-C00281
    Figure US20140179670A1-20140626-C00282
         		8 311 (M—OEt), 2.23 (min)
    141
    Figure US20140179670A1-20140626-C00283
    Figure US20140179670A1-20140626-C00284
         		1 1.23 (t, 6H, J = 7.2 Hz), 1.31 (s, 9H), 2.08 (s, 3H), 3.37 (s, 3H), 3.60-3.81 (m, 4H), 5.48 (s, 1H), 6.97-7.00 (m, 1H), 7.14 (t, 1H, J = 1.8 Hz), 7.42 (t, 1H, J = 7.5 Hz), 7.49 (dt, 1H, J = 8.4, 1.2 Hz)
    142
    Figure US20140179670A1-20140626-C00285
    Figure US20140179670A1-20140626-C00286
         		8 375 (M—OEt)/1.99 (min)
    143
    Figure US20140179670A1-20140626-C00287
         		Et 1 1.09-1.15 (m, 3H), 1.23 (t, 6H, J = 6.9 Hz), 2.02 (s, 3H), 3.68-3.85 (m, 4H), 3.98-4.06 (m, 2H), 5.48 (s, 1H), 7.44 (d, 1H, J = 6.9 Hz), 7.49 (s, 1H), l 7.67 (t, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 7.5 Hz)
    144
    Figure US20140179670A1-20140626-C00288
         		iPr 1 1.22 (t, 6H, J = 7.2 Hz), 1.45 (d, 6H, J = 6.9 Hz), 2.06 (s, 3H), 3.58-3.68 (m, 2H), 3.72-3.83 (m, 2H), 5.18 (s, 1H), 5.48 (s, 1H), 7.41 (d, 1H, J = 7.8 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 7.8 Hz)
    145
    Figure US20140179670A1-20140626-C00289
         		cPr 1 0.80-0.86 (m, 2H), 1.11 (q, 2H, J = 7.2 Hz), 1.23 (t, 6H, J = 7.2 Hz), 2.06 (s, 3H), 2.69-2.74 (m 1H), 3.58-3.68 (m, 2H), 3.73-3.81 (m, 2H), 5.47 (s, 1H), 7.39 (d, 1H, J = 7.5 Hz), 7.47 (s, 1H), 7.66 (t, 1H, J = 7.8 Hz), 7.75 (d, 1H, J = 7.8 Hz)
  • TABLE 17
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    146
    Figure US20140179670A1-20140626-C00290
    Figure US20140179670A1-20140626-C00291
         		1 1.22 (t, 6H, J = 7.2 Hz), 1.66-1.87 (m, 2H), 2.06 (s, 3H), 2.18-2.28 (m, 2H), 2.81-2.91 (m, 2H), 3.58-3.68 (m, 2H), 3.72-3.82 (m, 2H), 5.23 (quintet, 1H, J = 9.0 Hz), 5.47 (s, 1H), 7.41 (d, 1H, J = 8.1 Hz), 7.49 (s, 1H), 7.66 (t, 1H, J = 7.5 Hz), 7.75 (d, 1H, J = 7.8 Hz)
    147
    Figure US20140179670A1-20140626-C00292
    Figure US20140179670A1-20140626-C00293
         		1 1.18 (t, 6H, J = 6.9 Hz), 2.04 (s, 3H), 3.52-3.62 (m, 2H), 3.67-3.77 (m, 2H), 4.21 (t, 2H, J = 9.0 Hz), 4.40- 4.46 (m, 2H), 5.02 (s, 2H), 5.28-5.36 (m, 1H), 5.42 (s, 1H), 7.23-7.26 (m, 5H), 7.36 (d, 1H, J = 7.2 Hz), 7.43 (s, 1H), 7.63 (t, 1H, J = 7. Hz), 7.73 (d, 1H, J = 9.0 Hz)
    148
    Figure US20140179670A1-20140626-C00294
    Figure US20140179670A1-20140626-C00295
         		1 1.17-1.23 (m, 9H), 1.56 (d, 3H, J = 6.9 Hz), 2.09 (s, 3H), 3.56-3.66 (m, 2H), 3.71-3.81 (m, 2H), 4.07- 4.23 (m, 2H), 5.43-5.51 (m, 2H), 7.36-7.51 (m, 2H), 7.65 (t, 1H, J = 7.2 Hz), 7.74 (d, 1H, J = 7.8 Hz)
    149
    Figure US20140179670A1-20140626-C00296
    Figure US20140179670A1-20140626-C00297
         		1 1.22 (t, 6H, J = 8.1 Hz), 1.45 (d, 3H, J = 7.5 Hz), 1.99 (s, 3H), 2.08 (s, 3H), 3.57-3.80 (m, 4H), 4.20-4.34 (m, 1H), 4.58-4.70 (m, 1H), 5.25 (brs, 1H), 5.74 (s, 1H), 7.39-7.52 (m, 2H), 7.62-7.81 (m, 2H)
    150
    Figure US20140179670A1-20140626-C00298
    Figure US20140179670A1-20140626-C00299
         		4 1.25 (t, 6H, J = 7.1 Hz), 1.87 (d, 3H, J = 7.2 Hz), 2.08 (s, 3H), 3.62-3.67 (m, 2H), 3.75-3.82 (m, 2H), 5.49 (s, 1H), 6.29-6.35 (m, 1H), 7.24-7.33 (m, 3.5H), 7.42- 7.50 (m, 3H), 7.60-7.72 (m, 1.5H), 7.72-7.75 (m, 1H)
    151
    Figure US20140179670A1-20140626-C00300
    Figure US20140179670A1-20140626-C00301
         		1 1.23 (t, 6H, J = 7.2 Hz), 1.97 (s, 3H), 2.10 (s, 3H), 3.58- 3.69 (m, 2H), 3.72-3.83 (m, 2H), 4.22-4.27 (m, 2H), 4.31-4.36 (m, 2H), 5.48 (s, 1H), 7.38 (d, 1H, J = 9.0 Hz), 7.50 (s, 1H), 7.67 (t, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 7.5 Hz)
    • Reference Examples 152-153
  • The compounds 1g indicated in the below-mentioned table (Reference Examples 152-153) were obtained by using the compounds of Reference Examples 93-94 or known compounds according to the similar reaction or treatment method to those described in Reference Example 61.
  • Figure US20140179670A1-20140626-C00302
  • TABLE 18
    Ref. Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    152
    Figure US20140179670A1-20140626-C00303
    Figure US20140179670A1-20140626-C00304
         		1 1.15 (t, 6H, J = 7.1 Hz), 2.55 (s, 3H), 2.98 (s, 3H), 3.31 (s, 3H), 2.08 (s, 3H), 3.50 (q, 1H, J = 7.1 Hz), 3.53 (q, 1H, J = 7.1 Hz), 3.66 (q, 1H, J = 7.1 Hz), 3.69 (q, 1H, J = 7.1 Hz), 5.34 (s, 1H), 7.31 (d, 1H, J = 7.9 Hz), 7.40 (s, 1H), 7.48 (t, 1H, J = 7.9 Hz), 7.56 (d, 1H, J = 7.9 Hz), 8.33 (s, 1H)
    153
    Figure US20140179670A1-20140626-C00305
    Figure US20140179670A1-20140626-C00306
         		1 0.94 (t, 3H, J = 7.5 Hz), 1.22 (t, 6H, J = 7.1 Hz), 1.65- 1.75 (m, 2H), 2.63 (s, 3H), 3.06 (s, 3H), 3.58 (q, 1H, J = 7.1 Hz), 3.60 (q, 1H, J = 7.1 Hz), 3.73 (q, 1H, J = 7.1 Hz), 3.76 (q, 1H, J = 7.1 Hz), 3.92 (t, 3H, J = 7.5 Hz), 5.41 (s, 1H), 7.64-7.70 (m, 2H), 8.08 (t, 1H, J = 1.8 Hz), 8.22-8.26 (m, 1H), 8.42 (s, 1H)
    • Reference Examples 154-162
  • The compounds 1h indicated in the below-mentioned Table (Reference Examples 154-162) were obtained by using the compounds of Reference Examples 103-110 and 119 or known compounds according to the similar reaction or treatment method to those described in Reference Example 61.
  • Figure US20140179670A1-20140626-C00307
  • TABLE 19
    Ref. Measurement 1H-NMR (δ PPM)
    Ex. Ar1 R1 R4 cond. (or LC-MS: [M + H]+/Rt)
    154
    Figure US20140179670A1-20140626-C00308
         		Me Et 9 379 [M—OEt]+/Rt = 1/12
    155
    Figure US20140179670A1-20140626-C00309
         		Me iPr 4 1.23-1.28 (m, 6H), 1.34 (d, 6H, J = 7.1 Hz), 2.49-2.57 (m, 1H), 3.38 (s, 3H), 3.66-3.72 (m, 2H), 3.79-3.85 (m, 2H), 5.52 (s, 1H), 7.42 (d, 1H, J = 8.0 Hz), 7.49 (s, 1H), 7.69 (t, 1H, J = 7.9 Hz), 7.79 (d, 1H, J = 7.9 Hz)
    156
    Figure US20140179670A1-20140626-C00310
         		Me NMe2 9 394 [M—OEt]+/Rt = 1/10
    157
    Figure US20140179670A1-20140626-C00311
         		H H 3 1.25 (t, 6H, J = 7.1 Hz), 3.59-3.68 (m, 2H), 3.74-3.83 (m, 2H), 5.46 (s, 1H), 7.57 (d, 1H, J = 8.1 Hz), 7.63 (s, 1H), 7.67 (s, 1H), 7.67 (t, 1H, J = 7.9 Hz), 7.74 (d, 1H, J = 7.8 Hz ), 8.63 (s, 1H)
    158
    Figure US20140179670A1-20140626-C00312
         		iPr H 1 1.18 (t, 6H, J = 6.9 Hz), 1.43 (d, 6H, J = 9.9 Hz), 3.52-3.62 (m, 2H), 3.67-3.77 (m, 2H), 5.17 (quip, 1H, J = 6.9 Hz), 5.39 (s, 1H), 7.49 (d, 1H, J = 7.8 Hz), 7.53 (s, 1H), 7.55 (s, 1H), 7.59 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 7.8 Hz)
    159
    Figure US20140179670A1-20140626-C00313
    Figure US20140179670A1-20140626-C00314
         		H 4 1.25 (t, 6H, J = 7.1 Hz), 1.49 (d, 3H, J = 6.9 Hz), 1.50 (d, 3H, J = 6.9 Hz), 2.26 (s, 3H), 3.59-3.66 (m, 2H), 3.76-3.81 (m, 2H), 5.24 (sept, 1H, J = 6.9 Hz), 5.46 (s, 1H), 7.45 (s, 1H), 7.47-7.50 (m, 2H), 7.64 (d, 1H, J = 7.9 Hz)
  • TABLE 20
    Ref. Measurement
    Ex. Ar1 R1 R4 cond. 1H-NMR (δ PPM)
    160
    Figure US20140179670A1-20140626-C00315
         		Me H 1 1.22 (t, 6H, J = 7.1 Hz), 3.40 (s, 3H), 3.59 (q, 1H, J = 7.0 Hz), 3.63 (q, 1H, J = 7.0 Hz), 3.75 (q, 1H, J = 7.1 Hz), 3.79 (q, 1H, J = 7.1 Hz), 5.44 (s, 1H), 7.53 (d, 1H, J = 7.9 Hz), 7.60-7.66 (m, 3H), 7.71 (d, 1H, J = 7.9 Hz)
    161
    Figure US20140179670A1-20140626-C00316
    Figure US20140179670A1-20140626-C00317
         		H 1 1.18 (t, 6H, J = 7.1 Hz), 1.37 (s, 9H), 1.50 (d, 3H, J = 7.1 Hz), 3.54 (q, 1H, J = 7.1 Hz), 3.57 (q, 1H, J = 7.1 Hz), 3.70 (q, 1H, J = 7.1 Hz), 3.73 (q, 1H, J = 7.1 Hz), 5.36- 5.42 (m, 2H ), 7.48 (d, 1H, J = 7.9 Hz), 7.51-7.63 (m, 3H), 7.66 (d, 1H, J = 8.0 Hz)
    162
    Figure US20140179670A1-20140626-C00318
    Figure US20140179670A1-20140626-C00319
         		H 1 1.18 (t, 6H, J = 7.1 Hz), 1.39 (d, 3H, J = 7.1 Hz), 3.55 (q, 1H, J = 7.1 Hz), 3.58 (q, 1H, J = 7.1 Hz), 3.70 (q, 1H, J = 7.1 Hz), 3.73 (q, 1H, J = 7.1 Hz), 3.79 (dd, 1H J = 1/1.8, 3.4 Hz), 3.98-4.05 (m, 1H), 5.12-5.22 (m, 1H), 5.39 (s, 1H), 7.39-7.63 (m, 4H), 7.64 (d, 1H, J = 7.9 Hz)
    • Reference Example 163
  • Figure US20140179670A1-20140626-C00320
  • A solution of tert-butyl 5-[5-(3,3-diethoxyprop-1-ynyl)-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentylcarbamate (45.3 mg) and 4-cyanophenylhydrazine hydrochloride salt (14.5 mg) in N,N-dimethy formamide (1.0 ml) solution was stirred at 40° C. for two and a half hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (Z)-tert-butyl 5-[5-[3-[2-(4-cyanophenyl)hydrazono]prop-1-ynyl]-4-methyl-2,6-dihydro-3-(3-trifluorophenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentylcarbamate (23.7 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.38-1.42 (m, 11H), 1.50-1.56 (m, 2H), 1.65-1.77 (m, 2H), 2.13 (s, 3H), 3.06-3.14 (m, 2H), 4.05 (t, 3H, J=7.4 Hz), 4.52 (brs, 1H), 6.59 (s, 1H), 7.33 (d, 2H, J=8.8 Hz), 7.47 (d, 1H, J=7.9 Hz), 7.53-7.56 (m, 3H), 7.70 (t, 1H, J=7.9 Hz), 7.79 (d, 1H, J=7.9 Hz), 10.35 (s, 1H)
    • Reference Examples 164-173
  • The compounds 1i indicated in the below-mentioned table (Reference Examples 164-173) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference examples 163.
  • Figure US20140179670A1-20140626-C00321
  • TABLE 21
    Ref. Measurement 1H-NMR (δ PPM)
    Ex. Ar1 Ar2 R1 cond. (or LC-MS: [M + H]+/Rt)
    164
    Figure US20140179670A1-20140626-C00322
    Figure US20140179670A1-20140626-C00323
         		Me 1 2.15 (s, 3H), 3.50 (s, 3H), 6.60 (s, 1H), 7.38 (d, 1H, J = 8.7 Hz), 7.47 (d, 1H, 8.7 Hz), 7.54-7.57 (m, 3H), 7.74 (d, 1H, J = 7.8 Hz), 7.79 (s, 1H), 10.38 (brs, 1H)
    165
    Figure US20140179670A1-20140626-C00324
    Figure US20140179670A1-20140626-C00325
         		Me 1 2.10 (s, 3H), 3.44 (s, 3H), 3.88 (s, 3H), 6.55 (s, 1H), 7.33 (d, 2H, J = 9.0 Hz), 7.38-7.41 (m, 1H), 7.51 (d, 2H, J = 7.2 Hz), 7.50 (t, 1H, J = 7.5 Hz), 7.88 (t, 1H, J = 2.1 Hz), 8.16 (dt, 1H, J = 8.1, J = 1.5 Hz), 10.35 (brs, 1H)
    166
    Figure US20140179670A1-20140626-C00326
    Figure US20140179670A1-20140626-C00327
         		Me 1 2.10 (s, 3H), 3.44 (s, 3H), 3.88 (s, 3H), 6.55 (s, 1H), 7.33 (d, 2H, J = 9.0 Hz), 7.38-7.41 (m, 1H), 7.51 (d, 2H, J = 7.2 Hz), 7.50 (t, 1H, J = 7.5 Hz), 7.88 (t, 1H, J = 2.1 Hz), 8.16 (dt, 1H, J = 8.1, J = 1.5 Hz), 10.35 (brs, 1H)
    167
    Figure US20140179670A1-20140626-C00328
    Figure US20140179670A1-20140626-C00329
         		Me 1 2.12 (s, 3H), 3.44 (s, 3H), 6.55 (s, 1H), 7.14-7.16 (m, 1H), 7.29-7.41 (m, 4H), 7.51 (d, 2H, J = 8.7 Hz), 7.64 (d, 1H, J = 8.4 Hz), 10.34 (brs, 1H)
    168
    Figure US20140179670A1-20140626-C00330
    Figure US20140179670A1-20140626-C00331
         		Me 8 418 (MH+)/2.46 (min)
    169
    Figure US20140179670A1-20140626-C00332
    Figure US20140179670A1-20140626-C00333
         		Me 1 2.10 (s, 3H), 3.50 (s, 3H), 6.50 (s, 1H), 7.04-7.15 (m, 1H), 7.30 (t, 1H, J = 7.8 Hz), 7.41-7.76 (m, 6H), 10.21 (brs, 1H)
    170
    Figure US20140179670A1-20140626-C00334
    Figure US20140179670A1-20140626-C00335
         		Me 1 2.11 (s, 3H), 2.35 (s, 3H), 3.36 (s, 3H), 6.77 (s, 1H), 7.43 (d, 1H, J = 8.4 Hz), 7.45 (d, 2H, J = 0.9 Hz), 7.49 (s, 1H), 7.63 (t, 1H, J = 1.2 Hz), 7.67 (d, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 7.8 Hz), 9.79 (brs, 1H)
    171
    Figure US20140179670A1-20140626-C00336
    Figure US20140179670A1-20140626-C00337
         		Me 1 2.09 (s, 3H), 2.36 (s, 3H), 3.42 (s, 3H), 6.53 (s, 1H), 6.98 (d, 2H, J = 1.5 Hz), 7.25-7.39 (m, 4H), 7.48 (d, 2H, J = 8.4 Hz), 10.37 (brs, 1H)
    172
    Figure US20140179670A1-20140626-C00338
    Figure US20140179670A1-20140626-C00339
         		Me 1 1.27 (s, 9H), 2.06 (s, 3H), 3.41 (s, 3H), 6.53 (s, 1H), 6.97- 7.01 (m, 1H), 7.15-7.19 (m, 1H), 7.29 (d, 2H, J = 8.7 Hz), 7.40 (t, 1H, J = 7.8 Hz), 7.45-7.48 (m, 3H), 10.37 (brs, 1H)
    173
    Figure US20140179670A1-20140626-C00340
    Figure US20140179670A1-20140626-C00341
         		Me 8 462 (MH+)/2.21 (min)
    • Reference Example 174
  • Figure US20140179670A1-20140626-C00342
  • To a solution of 5-(3,3-diethoxyprop-1-ynyl)-3-ethyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4 (H,3H)-dione (2.40 g) in acetonitrile (72 ml) were added 4-cyanophenylhydrazine (1.11 g) and concentrated sulfuric acid (0.30 ml) and the resulting mixture was stirred at room temperature for thirty minutes. The resulting mixture was cooled to 0° C. and thereto was added water (140 ml) dropwise, and the solids were collected by filtration and washed with water to afford (Z)-4-(2-(3-(3-ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)prop-2-yneylidene)hydrazinyl)benzonitrile (2.50 g) as brown solid.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.27 (t, 3H, J=7.2 Hz), 2.08 (s, 3H), 4.08 (q, 2H, J=7.2 Hz), 6.54 (s, 1H), 7.30 (d, 2H, J=9.0 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.48-7.51 (m, 3H), 7.65 (t, 1H, J=7.8 Hz), 7.75 (d, 1H, J=7.8 Hz), 10.33 (s, 1H)
    • Reference Examples 175-182
  • The compounds 1j indicated in the below-mentioned table (Reference Examples 175-182) was obtained by using the corresponding starting materials according to the similar method and treatment methods to those described in the Reference Example 174.
  • Figure US20140179670A1-20140626-C00343
  • TABLE 22
    Ref. Measure-
    ment
    Ex. Ar1 Ar2 R1 cond. 1H-NMR (δ PPM)
    175
    Figure US20140179670A1-20140626-C00344
    Figure US20140179670A1-20140626-C00345
         		iPr 1 1.53 (d, 6H, J = 6.9 Hz), 2.10 (s, 3H), 5.29 (septet, 1H, J = 7.2 Hz), 6.57 (s, 1H), 7.33 (d, 2H, J = 8.7 Hz), 7.46- 7.55 (m, 4H), 7.69 (t, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 10.40 (s, 1H)
    176
    Figure US20140179670A1-20140626-C00346
    Figure US20140179670A1-20140626-C00347
         		cPr 1 0.88-0.94 (m, 2H), 1.20 (q, 2H, J = 6.6 Hz), 2.12 (s, 3H), 2.80-2.88 (m, 1H), 6.59 (s, 1H), 7.37 (d, 2H, J = 8.7 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.52-7.57 (m, 3H), 7.70 (t, 1H, J = 7.5 Hz), 7.79 (d, 1H, J = 8.71 Hz), 10.40 (s, 1H)
    177
    Figure US20140179670A1-20140626-C00348
    Figure US20140179670A1-20140626-C00349
    Figure US20140179670A1-20140626-C00350
         		1 1.77-1.95 (m, 2H), 2.11 (s, 3H), 2.29-2.38 (m, 2H), 2.89-2.97 (m, 2H), 5.27-5.39 (m, 1H), 6.59 (s, 1H), 7.37 (d, 2H, J = 8.7 Hz), 7.46 (d, 1H, J = 8.1 Hz), 7.54-7.57 (m, 3H), 7.70 (t, 1H, J = 7.5 Hz), 7.79 (d, 1H, J = 7.5 Hz), 10.46 (s, 1H).
    178
    Figure US20140179670A1-20140626-C00351
    Figure US20140179670A1-20140626-C00352
    Figure US20140179670A1-20140626-C00353
         		1 2.08 (s, 3H), 4.27 (t, 2H, J = 9.0 Hz), 4.53 (t, 2H, J = 8.7 Hz), 5.00 (s, 0.5H), 5.04 (s, 1.5 Hz), 5.45-5.55 (m, 1H), 6.52 (s, 1H), 7.19-7.30 (m, 7H), 7.40-7.42 (m, 3H), 7.50 (s, 1H), 7.62-7.76 (m, 2H), 10.22 (s, 1H)
    179
    Figure US20140179670A1-20140626-C00354
    Figure US20140179670A1-20140626-C00355
    Figure US20140179670A1-20140626-C00356
         		1 1.23 (t, 3H, J = 6.9 Hz), 1.65 (d, 3H, J = 6.9 Hz), 2.12 (s, 3H), 4.15-4.30 (m, 2H), 5.56 (ddd, 1H, J = 14.1, 6.9, 2.4 Hz), 7.15 (d, 2H, J = 8.7 Hz), 7.36 (d, 2H, J = 9.0 Hz), 7.43-7.61 (m, 2H), 7.69 (t, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 10.03 (s, 1H)
    180
    Figure US20140179670A1-20140626-C00357
    Figure US20140179670A1-20140626-C00358
    Figure US20140179670A1-20140626-C00359
         		1 1.49 (d, 3H, J = 7.2 Hz), 1.99 (s, 3H), 2.14 (s, 3H), 4.29 (dt, 1H, J = 1/1.7, 2.1 Hz), 4.62-4.74 (m, 1H), 5.29 (brs, 1H), 7.04 (d, 2H, J = 8.7 Hz), 7.26 (s, 1H), 7.39-7.61 (m, 4H), 7.69 (t, 1H, J = 7.5 Hz), 7.77 (d, 1H, J = 7.8 Hz), 9.36 (s, 1H)
    181
    Figure US20140179670A1-20140626-C00360
    Figure US20140179670A1-20140626-C00361
    Figure US20140179670A1-20140626-C00362
         		4 1.95 (d, 1.5H, J = 7.2 Hz), 1.96 (d, 1.5H, J = 7.2 Hz), 2.13 (s, 3H), 6.37-6.42 (m, 1H), 6.60 (s, 1H), 7.29- 7.37 (m, 5.5H), 7.49-7.52 (m, 3H), 7.55-7.58 (m, 2.5H), 7.63-7.75 (m, 1H), 7.78-7.80 (m, 1H), 10.44 (s, 1H)
    182
    Figure US20140179670A1-20140626-C00363
    Figure US20140179670A1-20140626-C00364
    Figure US20140179670A1-20140626-C00365
         		1 1.94 (s, 3H), 2.15 (s, 3H), 4.36-4.44 (m, 4H), 6.60 (d, 1H, J = 4.5 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.54-7.57 (m 3H), 7.71 (t, 1H, J = 7.8 Hz), 7.80 (d, 1H, J = 7.5 Hz), 10.38 (s, 1H)
    • Reference Examples 183-188
  • The compounds 1k indicated in the below-mentioned table (Reference Examples 183-188) were obtained by using the corresponding starting materials according to the similar reaction and method treatment to those described in Reference Example 174.
  • Figure US20140179670A1-20140626-C00366
  • TABLE 23
    Measure-
    Ref. ment
    Ex. Ar1 Ar2 R1 R4 cond. 1H-NMR (δ PPM)
    183
    Figure US20140179670A1-20140626-C00367
    Figure US20140179670A1-20140626-C00368
         		Me Et 4 1.10 (t, 3H, J = 7.6 Hz), 2.50 (q, 2H, J = 7.6 Hz), 3.51 (s, 3H), 6.63 (s, 1H), 7.37-7.41 (m, 2H), 7.51 (d, 1H, J = 7.9 Hz), 7.55-7.59 (m, 3H), 7.74 (t, 1H, J = 7.9 Hz), 7.83 (d, 1H, J = 7.81 Hz), 10.44 (s, 1H)
    184
    Figure US20140179670A1-20140626-C00369
    Figure US20140179670A1-20140626-C00370
         		Me iPr 4 1.38 (d, 3H, J = 7.0 Hz), 1.39 (d, 3H, J = 7.0 Hz), 2.51 (sept, 1H, J = 7.0 Hz), 3.52 (s, 3H), 6.66 (s, 1H), 7.40 (dd, 2H, J = 7.0, 1.8 Hz), 7.46 (d, 1H, 7.8 Hz), 7.53 (s, 1H), 7.57 (dd, 2H, J = 7.0, 1.8 Hz), 7.73 (t, 1H, J = 7.9 Hz), 7.83 (d, 1H, J = 7.9 Hz), 10.76 (s, 1H)
    185
    Figure US20140179670A1-20140626-C00371
    Figure US20140179670A1-20140626-C00372
         		H H 5 6.93 (s, 0.75H), 7.06 (d, 0.5H, J = 8.8 Hz), 7.29 (d, 1.5H, J = 8.8 Hz), 7.38 (s, 0.25H), 7.63 (d, 0.5H, J = 8.8 Hz), 7.70 (d, 1.5H, J = 8.8 Hz), 7.72-7.89 (m, 3H), 7.95 (s, 0.25H), 8.01 (s, 0.75H), 8.36 (s, 0.25H), 8.52 (s, 0.75H), 10.36 (s, 0.75H), 11.37 (s, 0.25H), 11.94 (s, 0.25H), 12.20 (s, 0.75H) (Z/E = 3/1)
    186
    Figure US20140179670A1-20140626-C00373
    Figure US20140179670A1-20140626-C00374
         		iPr H 1 1.57 (d, 6H, J = 5.1 Hz), 4.37 (quin, 1H, J = 6.6 Hz), 6.58 (s, 1H), 7.33 (d, 2H, J = 8.4 Hz), 7.51-7.69 (m, 6H), 7.74 (d, 1H, J = 6.61 Hz), 10.24 (s, 1H)
    187
    Figure US20140179670A1-20140626-C00375
    Figure US20140179670A1-20140626-C00376
    Figure US20140179670A1-20140626-C00377
         		H 1 1.52 (d, 3H, J = 7.2 Hz), 3.92 (dd, 1H, J = 1/1.7, 4.2 Hz), 4.20 (dd, 1H, J = 1/1.7, 8.4 Hz), 5.35 (brs, 1H), 6.58 (s, 1H), 7.29 (d, 2H, J = 6.9 Hz), 7, 54-7.60 (m, 3H), 7.65 (brs, 2H), 7.69 (d, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 8.1 Hz), 10.08 (s, 1H)
    188
    Figure US20140179670A1-20140626-C00378
    Figure US20140179670A1-20140626-C00379
    Figure US20140179670A1-20140626-C00380
         		H 4 1.58 (d, 3H, J = 6.9 Hz), 1.59 (d, 3H, J = 6.9 Hz), 2.30 (s, 3H), 5.36 (sept, 1H, J = 6.9 Hz), 6.60 (s, 1H), 7.35 (dd, 2H, J = 1.8, 7.0 Hz), 7.51 (s, 1H), 7.51-7.53 (m, 2H), 7.58 (dd, 2H, J = 1.8, 7.0 Hz), 7.68 (d, 1H, J = 8.8 Hz), 10.27 (s, 1H)
    • Reference Example 189
  • Figure US20140179670A1-20140626-C00381
  • 5-Iodo-3-isopropyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 85) (600 mg) and 2-bromo-3-pyridine boronic acid pinacol ester (878 mg) were dissolved in 1,2-dimethoxyethane (30 ml). Thereto were added under nitrogen atmosphere water (6 ml), sodium carbonate (290 mg), 2-(dicyclohexylphosphino)biphenyl (57.6 mg) and tetrakis(triphenylphosphine)palladium (316 mg) and the resulting mixture was stirred with heating under reflux for four and a half hours. The reaction solution was concentrated under reduced pressure and to the residue was added water, and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(2-bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (134 mg).
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.52 (d, 6H, J=6.9 Hz), 1.68 (s, 3H), 5.23 (sept, 1H, J=6.9 Hz), 7.35-7.39 (m, 1H), 7.50-7.59 (m, 1H), 7.60-7.66 (m, 2H), 7.67-7.73 (m, 1H), 7.77 (d, 1H, J=7.9 Hz), 8.40 (dd, 1H, J=2.2, 4.7 Hz)
    • Reference Example 190
  • Figure US20140179670A1-20140626-C00382
  • The compound was prepared by using the corresponding starting materials according to the similar reaction and treatment method to those described in the Reference Example 189.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.84 (s, 3H), 3.42 (s, 3H), 7.08 (dd, 1H, J=5.0, 1.3 Hz), 7.25 (dd, 1H, J=3.0, 1.3 Hz), 7.38 (dd, 1H, J=5.0, 3.0 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.69 (t, 1H, J=7.8 Hz), 7.77 (d, 1H, J=7.8 Hz)
    • Reference Example 191
  • Figure US20140179670A1-20140626-C00383
  • The compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 189.
  • LC-Mass: 396 (MH+)/7.60 (min) (measurement condition 7)
    • Reference Examples 192-193
  • Figure US20140179670A1-20140626-C00384
    • Step 1 Reference Example 192
  • To concentrated sulfuric acid (2.0 ml) were added in ice bath fuming nitric acid (0.2 ml), 6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 21) (200.0 mg) and the resulting mixture was stirred for three hours in ice bath. The reaction mixture was poured into ice water, and the precipitated solids were collected by filtration to afford 6-methyl-5-nitro-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (219.0 mg).
  • 1H-NMR (CDCl3: 400 MHz) (δ PPM):
  • 0.97 (t, 3H, J=7.4 Hz), 1.66-1.76 (m, 2H), 2.04 (s, 3H), 3.95 (t, 2H, J=7.4 Hz), 7.49 (d, 1H, J=7.9 Hz), 7.57 (s, 1H), 7.74 (t, 1H, J=7.9 Hz), 7.49 (d, 1H, J=7.9 Hz)
    • Step 2 Reference Example 193
  • To a solution of 6-methyl-5-nitro-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (200.0 mg) in methanol (10.0 ml) was added palladium hydrate (20.0 mg) and the resulting mixture was stirred at room temperature under catalytic hydrogenation condition for twelve hours. The reaction mixture was degassed and then filtered through Celite (trade mark), and then concentrated under reduced pressure to afford 5-amino-6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4 (1H,3H)-dione (190.0 mg).
  • 1H-NMR (CDCl3: 400 MHz) (δ PPM):
  • 0.96 (t, 3H, J=7.4 Hz), 1.66-1.75 (m, 2H), 1.82 (s, 3H), 3.32 (brs, 2H), 3.97 (t, 2H, J=7.4 Hz), 7.45 (d, 1H, J=7.8 Hz), 7.51 (s, 1H), 7.65 (t, 1H, J=7.8 Hz), 7.73 (d, 1H, J=7.8 Hz)
    • Reference Examples 194-196
  • The compounds 1l indicated in the below-mentioned Table (Reference Examples 194-196) were obtained by using the corresponding starting materials according to the similar reaction and treatment method described in Reference Example 192.
  • Figure US20140179670A1-20140626-C00385
  • TABLE 24
    Ref. Measurement 1H-NMR (δ PPM)
    Ex. R1 R4 cond. (or LC-MS: [M + H]+ /Rt)
    194 iPr H 1 1.46 (d, 6H, J = 6.8 Hz), 5.17-5.26
    (m, 1H), 7.55 (d, 1H, J = 8.4 Hz),
    7.63-7.68 (m, 2H), 7.75 (d, 1H, J =
    7.9 Hz), 8.66 (s, 1H)
    195 iPr Me 7 358 (M + H)/3.48 (min)
    196 Me Me 7 330 (M + H)/3.04 (min)
    • Reference Example 197
  • The compounds 1m indicated in the below-mentioned table (Reference Example 197) was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 193.
  • Figure US20140179670A1-20140626-C00386
  • TABLE 25
    Ref. Measurement
    Ex. R1 R4 cond. 1H-NMR (δ PPM)
    197 iPr H 4 1.52 (d, 6H, J = 6.9 Hz), 5.28 (sept,
    1H, J = 6.9 Hz),
    6.79 (s, 1H), 7.57-7.61 (m, 2H), 7.63-
    7.66 (m, 2H)
    • Reference Example 198
  • Figure US20140179670A1-20140626-C00387
  • To a solution of 4-amino-3-(methylthio)benzonitrile (71.1 mg) and 5N aqueous hydrochloric acid (2.0 ml)/ethanol (0.5 ml) was added under ice cooling sodium nitrite (32.5 mg) and the resulting mixture was stirred for one and a half hours. To the reaction mixture was added tin(II) chloride (101.4 mg) and the resulting mixture was stirred at 0° C. for two and a half hours. The reaction mixture was filtered, and the mother liquor was basified (pH=about 10) with potassium carbonate and extracted with chloroform (30 ml) three times, and the organic layer was dried over sodium sulfate and then concentrated under reduced pressure to afford 4-hydrazinyl-3-(methylthio)benzonitrile (57.7 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 2.28 (s, 3H), 3.69 (brs, 2H), 6.59 (brs, 1H), 7.12 (d, 1H, J=8.4 Hz), 7.50 (d, 1H, J=1.8 Hz), 7.41 (ddd, 1H, J=8.7, 2.7, 0.6 Hz), J=1.8 Hz)
    • Reference Example 199
  • Figure US20140179670A1-20140626-C00388
  • To a solution of 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 60) (60.0 mg), 2-thiophen boronic acid (84.6 mg), sodium carbonate (84.6 mg) in tetrahydrofuran (2.0 ml)/water (0.3 ml) was added tetrakis(triphenylphosphine)palladium (25.2 mg) and the resulting mixture was stirred with heating under reflux for five hours. The reaction mixture was filtered through Celite (trade mark) and thereto was added water (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (27.3 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.84 (s, 3H), 3.42 (s, 3H), 7.08 (dd, 1H, J=5.0, 1.3 Hz), 7.25 (dd, 1H, J=3.0, 1.3 Hz), 7.38 (dd, 1H, J=5.0, 3.0 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.69 (t, 1H, J=7.8 Hz), 7.77 (d, 1H, J=7.8 Hz)
    • Reference Example 200
  • Figure US20140179670A1-20140626-C00389
  • To a solution of 3,6-dimethyl-5-(thiophen-3-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference example 199) (30.7 mg) in acetic acid (1.5 ml) was added N-bromosuccinimide (20.2 mg) and the resulting mixture was stirred at room temperature for three hours. To the reaction mixture were added an aqueous saturated sodium hydrogen carbonate solution (10 ml) and an aqueous saturated sodium thiosulfate solution (10 ml), and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (17.4 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.77 (s, 3H), 3.42 (s, 3H), 6.92 (dd, 1H, J=5.7, 3.3 Hz), 7.34 (dd, 1H, J=5.7, 1.5 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.59 (brd, 1H, J=10.0 Hz), 7.66-7.72 (m, 1H), 7.78 (d, 1H, J=7.8 Hz)
    • Reference Examples 201-202
  • The compounds 1n indicated in the below-mentioned table (Reference Examples 201-202) were obtained by using the corresponding starting materials and according to the similar reaction and treatment method to those described in Reference Example 199.
  • Figure US20140179670A1-20140626-C00390
  • TABLE 26
    Ref. Measurement
    Ex. L′ R1 cond. 1H-NMR (δ PPM)
    201
    Figure US20140179670A1-20140626-C00391
    Figure US20140179670A1-20140626-C00392
         		1 2.13 (s, 3H), 3.45 (s, 3H), 6.18-6.21 (m, 1H), 6.26-6.29 (m, 1H), 6.89-6.92 (m, 1H), 7.40 (brd, 1H, J = 7.8 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.57 (s, 1H), 7.69 (t, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 7.8 Hz)
    202
    Figure US20140179670A1-20140626-C00393
    Figure US20140179670A1-20140626-C00394
         		4 0.95 (t, 3H, J = 7.4 Hz), 1.66-1.75 (m, 2H), 1.84 (s, 3H), 2.00-2.07 (m, 1H), 2.11-2.22 (m, 1H), 2.24-2.35 (m, 1H), 2.70-2.85 (m, 2H), 2.90-3.00 (m, 1H), 3.92 (t, 3H, J = 7.4 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.53 (s, 0.5H), 7.57 (s, 0.5H), 7.64-7.69 (m, 1H), 7.75 (d, 1H, J = 7.8 Hz)
    • Reference Example 203 4-[3-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]thiophen-2-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00395
  • To a solution of 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 200) (17.0 mg), 4-cyanophenylboronic acid (11.2 mg) and sodium carbonate (20.2 mg) in tetrahydrofuran (1.0 ml)/water (0.2 ml) was added tetrakis(triphenylphosphine)palladium (4.4 mg) and the resulting mixture was stirred with heating under reflux for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[3-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]thiophen-2-yl]benzonitrile (16.4 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.43 (s, 1.5H), 1.45 (s, 1.5H), 3.43 (s, 1.5H), 3.44 (s, 1.5H), 7.05 (d, 0.5H, J=3.4 Hz), 7.07 (d, 0.5H, J=3.4 Hz), 7.16 (d, 0.5H, J=8.5 Hz), 7.21 (s, 0.5H), 7.46-7.55 (m, 4H), 7.61-7.74 (m, 4H)
    • Reference Example 204 4-[2-[6-Methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]cyclopent-1-enyl]benzonitrile
  • Figure US20140179670A1-20140626-C00396
  • The intended compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 203.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 0.96 (t, 3H, J=7.4 Hz), 1.44 (s, 1.5H), 1.46 (s, 1.5H), 1.66-1.76 (m, 2H), 2.04-2.20 (m, 2H), 2.40-2.52 (m, 1H), 2.75-2.85 (m, 1H), 2.95-3.10 (m, 2H), 3.96 (brt, 2H, J=6.6 Hz), 7.12-7.18 (m, 1H), 7.31-7.46 (m, 3H), 7.52-7.65 (m, 3H), 7.71 (d, 1H, J=8.1 Hz)
    • Reference Example 205 4-[2-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrrol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00397
  • A solution of 3,6-dimethyl-5(1H-pyrrol-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 201) (20.0 mg), 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) in 1,4-dioxane (2.0 ml) was stirred with heating under reflux for fifteen hours. Thereto were added 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) and the resulting mixture was stirred with heating under reflux for four hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: hexane/acetone/methanol) to afford 4-[2-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrrol-1-yl]benzonitrile (8.2 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.68 (s, 1.5H), 1.72 (s, 1.5H), 3.30 (s, 1.5H), 3.32 (s, 1.5H), 6.31-6.34 (m, 1H), 6.41-6.44 (m, 1H), 6.98-7.00 (m, 1H), 7.26-7.38 (m, 3H), 7.46 (d, 0.5H, J=8.1 Hz), 7.56 (s, 0.5H), 7.63-7.77 (m, 4H)
    • Reference Examples 207-210
  • The compounds indicated in the below-mentioned table (Reference Examples 207-210) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 1-18.
  • Figure US20140179670A1-20140626-C00398
  • TABLE 27
    Ref. Measurement
    Ex. R1 cond. (LC-MS: [M + H]+/Rt
    207
    Figure US20140179670A1-20140626-C00399
         		9 408 (M + H)/1.06 (min)
    208
    Figure US20140179670A1-20140626-C00400
         		9 408 (M + H)/1.06 (min)
    209
    Figure US20140179670A1-20140626-C00401
         		9 422 (M + H)/1.06 (min)
    210
    Figure US20140179670A1-20140626-C00402
         		9 422 (M + H)/1.06 (min)
    • Reference Examples 211-216
  • The compounds indicated in the below-mentioned table (Reference Examples 211-216) were obtained by using the corresponding 616 starting materials according to the similar reaction and treatment method to those described in Reference Examples 20-51 or J. Med. Chem. 2008, 51, 7478.
  • Figure US20140179670A1-20140626-C00403
  • TABLE 28
    Measure-
    Ref. ment
    Ex. R1 cond. (LC-MS: [M + H]+/Rt)
    211
    Figure US20140179670A1-20140626-C00404
         		9 474 (M + H)/1.08 (min)
    212
    Figure US20140179670A1-20140626-C00405
         		9 474 (M + H)/1.08 (min)
    213
    Figure US20140179670A1-20140626-C00406
         		9 488 (M + H)/1.07 (min)
    214
    Figure US20140179670A1-20140626-C00407
         		9 488 (M + H)/1.09 (min)
    215
    Figure US20140179670A1-20140626-C00408
         		9 488 (M + H)/1.09 (min)
    216 H 9 271 (M + H)/0.70 (min)
    • Reference Examples 217-223
  • The compounds indicated in the below-mentioned table (Reference Examples 217-223) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 60.
  • Figure US20140179670A1-20140626-C00409
  • TABLE 29
    Measure-
    Ref. ment
    Ex. R1 cond. (LC-MS: [M + H]+/Rt)
    217
    Figure US20140179670A1-20140626-C00410
         		9 600 (M + H)/1.20 (min)
    218
    Figure US20140179670A1-20140626-C00411
         		9 600 (M + H)/1.20 (min)
    219
    Figure US20140179670A1-20140626-C00412
         		9 614 (M + H)/1.19 (min)
    220
    Figure US20140179670A1-20140626-C00413
         		9 614 (M + H)/1.20 (min)
    221
    Figure US20140179670A1-20140626-C00414
         		9 614 (M + H)/1.20 (min)
    222
    Figure US20140179670A1-20140626-C00415
         		9 518 (M + H)/0.896 (min)
    223 H 9 397 (M + H)/0.84 (min)
    • Reference Examples 224-230
  • The compounds indicated in the below-mentioned table (Reference Examples 224-230) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 61.
  • Figure US20140179670A1-20140626-C00416
  • TABLE 30
    . Measure-
    Ref. ment
    Ex. R1 cond. (LC-MS: [M + H]+/Rt)
    224
    Figure US20140179670A1-20140626-C00417
         		9 554 (M − OEt)/1.27 (min)
    225
    Figure US20140179670A1-20140626-C00418
         		9 554 (M − OEt)/1.27 (min)
    226
    Figure US20140179670A1-20140626-C00419
         		9 568 (M − OEt)/0.89 (min)
    227
    Figure US20140179670A1-20140626-C00420
         		9 568 (M − OEt)/1.25 (min)
    228
    Figure US20140179670A1-20140626-C00421
         		9 554 (M − OEt)/1.27 (min)
    229
    Figure US20140179670A1-20140626-C00422
         		9 472 (M − OEt)/1.005 (min)
    230 H 9 397/0.836 (min)
    • Reference Examples 231-237
  • The compounds indicated in the below-mentioned table (Reference Examples 231-237) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 174.
  • Figure US20140179670A1-20140626-C00423
  • TABLE 31
    Measure-
    Ref. ment
    Ex. R1 cond. (LC-MS: [M + H]+/Rt)
    231
    Figure US20140179670A1-20140626-C00424
         		9 641 (M + H)/1.17 (min)
    232
    Figure US20140179670A1-20140626-C00425
         		9 641 (M + H)/1.17 (min)
    233
    Figure US20140179670A1-20140626-C00426
         		9 655 (M + H)/1.16 (min)
    234
    Figure US20140179670A1-20140626-C00427
         		9 655 (M + H)/1.17 (min)
    235
    Figure US20140179670A1-20140626-C00428
         		9 655 (M + H)/1.17 (min)
    236
    Figure US20140179670A1-20140626-C00429
         		9 559 (M + H)/1.121 (min)
    237 H 9 438 (M + H)/1.066 (min)
    • Reference Examples 238-239
  • Figure US20140179670A1-20140626-C00430
    • Step 1 Reference Example 238
  • The above-mentioned nitro compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 192. UPLC/MS 344 (M+H)/0.987 min. (measurement condition 9)
    • Step 2 Reference Example 239
  • The above-mentioned amino compounds was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 193. UPLC/MS 314 (M+H)/0.759 min. (measurement condition 9)
    • Reference Example 240
  • Figure US20140179670A1-20140626-C00431
  • A solution of 5-amino-3-ethyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 239) (200 mg), 3-methoxypropionic acid (0.15 ml), HATU (487 mg), HOAT (174 mg) and diisopropylethyl amine (0.21 ml) in DMF (5.0 ml) was stirred at room temperature for two hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned N-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methoxypropaneamide (222 mg). UPLC/MS 400 (M+H)/0.754 min. (measurement condition 9)
  • The compounds indicated in the below-mentioned table (Reference Examples 241-242) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 240.
  • Figure US20140179670A1-20140626-C00432
  • TABLE 32
    Measure-
    Ref. ment
    Ex. R cond. (LC-MS: [M + H]+/Rt)
    241
    Figure US20140179670A1-20140626-C00433
         		9 456 (M + H)/0.990 (min)
    242
    Figure US20140179670A1-20140626-C00434
         		9 440 (M + H)/0.574 (min)
    • Reference Examples 243-249
  • Figure US20140179670A1-20140626-C00435
    • Step 1 Reference Example 243
  • The compound obtained in Reference Example 239 (316 mg) was dissolved in methylene chloride (10 ml) and thereto was added at 0° C. methyl chloroglyoxylate (0.31 ml) and the resulting mixture was stirred for twenty minutes. To the reaction solutions were added water (30 ml) and chloroform (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford the above-mentioned methyl 2-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-2-oxoacetate (410 mg). UPLC/MS 400 (M+H)/0.77 min. (measurement condition 9)
    • Step 2 Reference Example 244
  • The compound obtained in Reference Example 243 (410 mg) was dissolved in toluene (10 ml) and thereto was added Lawesson's reagent (624 mg), and the resulting mixture was stirred at 80° C. for one hour. The precipitates were filtered and the filtrates were concentrated under reduced pressure, and thereto were then added water (30 ml) and ethyl acetate/hexane=2/1 (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned methyl 2-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-2-thioxo acetate (413 mg). UPLC/MS 416 (M+H)/0.89 min. (measurement condition 9)
  • The compounds indicated in the below-mentioned table (Reference Examples 245-247) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 244.
    • Reference Example 245
  • Figure US20140179670A1-20140626-C00436
  • TABLE 33
    Measure-
    Ref. ment
    Ex. R cond. (LC-MS: [M + H]+/Rt)
    245
    Figure US20140179670A1-20140626-C00437
         		9 472 (M + H)/1.092 (min)
    246
    Figure US20140179670A1-20140626-C00438
         		9 455 (M + H)/0.669 (min)
    247
    Figure US20140179670A1-20140626-C00439
         		9 416 (M + H)/0.880 (min)
    • Step 3 Reference Example 248
  • The compound obtained in Reference Example 244 (549 mg) was dissolved in DMF (5 ml) and thereto was added 28% ammonia water (4.79 ml) and the resulting mixture was stirred for forty minutes. To the reaction solution were added ethyl acetate (15 ml) and 20% aqueous citric acid solution (15 ml) followed by an addition of further ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned 2-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-ylamino)-2-oxoacetamide (318 mg). UPLC/MS 401 (M+H)/0.82 min. (measurement condition 9)
    • Reference Example 249
  • The below-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 248.
  • Figure US20140179670A1-20140626-C00440
  • UPLC/MS 429 (M+H)/0.810 min. (measurement condition 9)
    • Reference Examples 250-254
  • Figure US20140179670A1-20140626-C00441
    Figure US20140179670A1-20140626-C00442
    • Step 1 Reference Example 250
  • To a solution of the compound obtained in Reference Example 49 (1.0 g) in ethanol (10 ml) was added 1N aqueous sodium hydroxide solution (5.4 ml) and the resulting mixture was stirred at room temperature for two hours. To the reaction mixture was added water (10 ml) and thereto was then added ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned (R)-3-(1-hydroxypropan-2-yl)-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (880 mg). UPLC/MS 329 (M+H)/0.759 min (measurement condition 9)
    • Step 2 Reference Example 251
  • To a solution of the compound obtained in Reference Example 250 (2.0 g), imidazole (456 mg) and triphenylphosphine (1.7 g) in THF (30 ml) was added iodine (1.7 g) and the resulting mixture was stirred at room temperature for fifteen hours. To the reaction mixture was added 10% hypo water (30 ml) and thereto was then added ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned (R)-3-(1-iodopropane-2-yl)-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (2.0 g). UPLC/MS 439 (M+H)/1.038 min. (measurement condition 9)
    • Step 3 Reference Example 252
  • To a solution of the compound obtained in Reference Example 251 (4.0 g) in acetone (50 ml) was added thiourea (929 mg) and the resulting mixture was stirred at 70° C. for two hours (note: it was confirmed a formation of (R)-2-(4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propyl carbamidothioate of the above-mentioned intermediate: UPLC/MS 387 (M+H)/0.665 min). The reaction mixture was concentrated under reduced pressure and thereto were added sodium disulfite (1.7 g) and dichloromethane/water (50 ml/10 ml), and the resulting mixture was stirred with heating under reflux for one and a half hours. To the reaction mixture was added water (20 ml) and followed by an addition of ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford the above-mentioned (R)-3-(1-mercaptopropan-2-yl)-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (1.5 g). UPLC/MS 345 (M+H)/0.907 min. (measurement condition 9)
    • Step 4 Reference Example 253
  • To a solution of the compound obtained Reference Example 252 (3.0 g) in formic acid (20 ml) was added at 0° C. 30% aqueous hydrogen peroxide solution (0.98 ml) and the resulting mixture was stirred at room temperature for three hours. To the reaction mixture were added 10% hypo water (50 ml) and ethyl acetate (20 ml), and insoluble materials were then removed by filtration and the aqueous layer was washed with ethyl acetate (20 ml×2). To the aqueous layer was added chloroform/ethanol (10 ml/1.0 ml×10) such that the intended products were extracted into an organic layer, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford the above-mentioned (R)-2-(4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonic acid (1.2 g).
  • UPLC/MS 393 (M+H)/0.602 min. (measurement condition 9)
    • Step 5 Reference Example 254
  • To a solution of the compound prepared in Reference Example 253 (1.0 g) in acetonitrile (20 ml) was added phosphorus oxychloride (1.3 ml) and the resulting mixture was stirred at 60° C. for three hours (note: it was confirmed a formation of the above-mentioned intermediate, (R)-2-(4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonylchloride; UPLC/MS 41.3 (M+H)/0.980 min). The reaction solution was cooled to 0° C. and thereto was added ammonia water (5.0 ml) dropwise and the resulting mixture was stirred for one hour. To the reaction mixture was added water (30 ml) and thereto was added ethyl acetate (20 ml×3) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned (R)-2-(4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonamide (560 mg). UPLC/MS 392 (M+H)/0.753 min. (measurement condition 9)
    • Example 1
  • 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00443
  • A solution of 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 61) and 4-cyanophenylhydrazine hydrochloride (27.9 mg) in N,N-dimethy formamide (2.0 ml) was stirred at 130° C. for seven hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (17.9 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.63 (s, 1.5H), 1.68 (s, 1.5H), 3.30 (s, 1.5H), 3.35 (s, 1.5H), 6.46 (dd, 1H, J=7.5, 1.8 Hz), 7.30 (d, 0.5H, J=7.8 Hz), 7.38 (s, 0.5H), 7.48 (d, 0.5H, J=7.8 Hz), 7.55-7.59 (m, 2.5H), 7.63-7.79 (m, 4H), 7.80 (t, 1H, J=1.8 Hz)
    • Examples 2-18
  • The compounds indicated in the below-mentioned table (Examples 2-18) were prepared by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 1.
    • Example 2
  • 4-[5-[6-methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 3
  • 2-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]ethyl acetate ester
    • Example 4
  • 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid ethyl ester
    • Example 5
  • 4-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]butanoic acid ethyl ester
    • Example 6
  • 2-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]acetic acid benzyl ester
    • Example 7
  • 4-[5-[3-(2,2-dimethoxyethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 8
  • tert-butyl 5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethyl)-2,3-dihydropyridine-1(6H)-yl]pentylcarbamate
    • Example 9
  • 4-[5-[3-(4-methoxybenzyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 10
  • 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]benzonitrile
    • Example 11
  • 4-[5-[1-(3-fluorophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 12
  • 4-[5-[1-(3-methoxyphenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 13
  • 4-[5-[1-(4-fluoro-3-trifluorophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 14
  • 4-[5-(1-phenyl-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl]benzonitrile
    • Example 15
  • 4-[5-[3,6-dimethyl-2,4-dioxo-1-(2-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 16
  • 4-[5-[3,6-dimethyl-2,4-dioxo-1-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 17
  • 4-[5-[1-(3-chlorophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 18
  • 4-[5-[1-(3-nitrophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00444
  • TABLE 34
    Measure-
    ment
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    2
    Figure US20140179670A1-20140626-C00445
    Figure US20140179670A1-20140626-C00446
         		1 0.81 (t, 1.5H, J = 7.4 Hz), 0.82 (t, 1.5H, J = 7.4 Hz), 1.50-1.58 (m, 2H), 1.63 (s, 1.5H), 1.67 (s, 1.5H), 3.76-3.85 (m, 2H), 6.40 (d, 0.5H, J = 7.7 Hz), 6.41 (d, 0.5H, J = 7.7 Hz), 7.28 (d, 0.5H, J = 7.5 Hz), 7.36 (s, 0.5H), 7.41 (d, 0.5H, J = 7.5 Hz), 7.50-7.54 (m, 3.5H), 7.58-7.75 (m, 4H)
    3
    Figure US20140179670A1-20140626-C00447
    Figure US20140179670A1-20140626-C00448
         		1 1.23 (t, 3H, J = 6.0 Hz), 1.61 (s, 1.5H), 1.66 (s, 1.5H), 4.18 (dq, 2H, J = 6.9, 1.8 Hz), 4.65 (t, 2H, J = 3.0 Hz), 6.47 (dd, 1H, J = 7.5, 2.1 Hz), 7.31-7.38 (m, 0.5H), 7.41-7.47 (m, 1.5H), 7.52-7.66 (m, 4H), 7.70-7.77 (m, 3H)
    4
    Figure US20140179670A1-20140626-C00449
    Figure US20140179670A1-20140626-C00450
         		1 1.18 (t, 3H, J = 3.0 Hz), 1.55 (s, 1.5H), 1.60 (s, 1.5H), 2.48-2.56 (m, 2H), 3.99-4.07 (m, 2H), 4.13-4.27 (m, 2H), 6.42 (dd, 2H, J = 6.0, 3.0 Hz), 7.21-7.75 (m, 9H)
    5
    Figure US20140179670A1-20140626-C00451
    Figure US20140179670A1-20140626-C00452
         		1 1.17 (t, 3H, J = 3.0 Hz), 1.59 (s, 1.5H) 1.63 (s, 1.5H), 1.83-1.92 (m, 2H), 2.26 (t, 2H, J = 6.0 Hz), 3.86-4.00 (m, 4H), 6.42 (dd, 1H, J = 6.0, 3.0 Hz), 7.25-7.75 (m, 9H)
    6
    Figure US20140179670A1-20140626-C00453
    Figure US20140179670A1-20140626-C00454
         		1 1.60 (s, 1.5H), 1.65 (s, 1.5H), 4.67-4.82 (m, 2H), 5.12-5.22 (m, 2H), 6.47 (d, 0.5H, J = 7.0 Hz), 6.48 (d, 0.5H, J = 7.0 Hz), 7.30-7.38 (m, 6.5H), 7.45 (d, 0.5H, J = 8.1 Hz), 7.52-7.58 (m, 2H), 7.62-7.69 (m, 3H), 7.76 (d, 1H, J = 8.1 Hz), 7.79 (t, 1H, J = 1.8 Hz)
  • TABLE 35
    Measure-
    ment
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    7
    Figure US20140179670A1-20140626-C00455
    Figure US20140179670A1-20140626-C00456
         		1 1.60 (s, 1.5H), 1.65 (s, 1.5H), 3.20 (s, 1.5H), 3.21 (s, 1.5H), 3.26 (s, 1.5H), 3.28 (s, 1.5H), 3.94- 4.12 (m, 2H), 4.64 (dd, 1H, J = 10.5, 4.8 Hz), 6.41 (d, 0.5H, J = 8.3 Hz), 6.42 (d, 0.5H, J = 8.3 Hz), 7.28 (d, 0.5H, J = 7.9 Hz), 7.36 (s, 0.5H), 7.41 (d, 0.5H, J = 7.9 Hz), 7.49 (s, 0.5H), 7.51-7.56 (m, 3H), 7.58-7.75 (m, 4H)
    8
    Figure US20140179670A1-20140626-C00457
    Figure US20140179670A1-20140626-C00458
         		1 1.23-1.52 (m, 13H), 1.64-1.70 (m, 2H), 2.16 (s, 3H), 3.04-3.11 (m, 2H), 3.96 (t, 2H, J = 7.7 Hz), 4.51 (brs, 1H), 7.06 (d, 1H, J = 8.8 Hz), 7.21 (s, 1H), 7.44-7.58 (m, 4H), 7.65-7.79 (m, 3H), 8.53 (s, 1H)
    9
    Figure US20140179670A1-20140626-C00459
    Figure US20140179670A1-20140626-C00460
         		1 1.69 (s, 1.5H), 1.73 (s, 1.5H), 3.80 (s, 3H), 4.93 (dd, 1H, J = 13.5, 4.2 Hz) 5.02 (dd 1H, J = 13.5, 7.8 Hz), 6.44 (dd, 1H, J = 9.0, 3.0 Hz), 6.79 (d, 2H, 9.0), 7.26-7.29 (m, 2H), 7.51-7.55 (m, 3H), 7.62-7.68 (m, 4H), 7.74-7.76 (m, 1H), 7.78 (t, 1H, J = 1.5 Hz)
    10
    Figure US20140179670A1-20140626-C00461
    Figure US20140179670A1-20140626-C00462
         		4 1.58 (s, 1.5H), 1.66 (s, 1.5H), 3.28 (s, 1.5H), 3.30 (s, 1.5H), 6.38 (d, 0.5H, J = 1.8 Hz), 6.42 (d, 0.5H, J = 1.8 Hz), 7.27-7.32 (s, 0.5H), 7.43-7.55 (m, 3.5H), 7.57-7.72 (m, 3H), 7.73-7.77 (m, 2H)
    11
    Figure US20140179670A1-20140626-C00463
    Figure US20140179670A1-20140626-C00464
         		1 1.64 (s, 1.5H), 1.68 (s, 1.5H), 3.33 (s, 1.5H),3.35 (s, 1.5H), 6.45 (dd, 1H, J = 4.2, 1.8 Hz), 6.83-6.89 (m, 1H), 6.99-7.07 (m, 1H), 7.21 (d, 1H, J = 8.1 Hz), 7.49 (t, 1H, J = 6.0 Hz), 7.57 (d, 2H, J = 8.4 Hz), 7.71 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.1 Hz), 7.79 (t, 1H, J = 1.5 Hz)
  • TABLE 36
    Measure-
    ment
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    12
    Figure US20140179670A1-20140626-C00465
    Figure US20140179670A1-20140626-C00466
         		4 1.60 (s, 1.5H), 1.61 (s, 1.5H), 3.30 (s, 3H), 3.75 (s, 1.5 H), 3.77 (s, 1.5 H), 6.39-6.41 (m, 1H), 6.51 (t, 0.5H, J = 2.2 Hz), 6.56-6.58 (m, 0.5H), 6.71 (t, 0.5H, J = 2.3 Hz), 6.75-6.78 (m, 0.5H), 6.92-6.97 (m, 1H), 7.32-7.38 (m, 1H), 7.50-7.54 (m, 2H), 7.65-7.68 (m, 2H), 7.74 (d, 1H, J = 1.8 Hz)
    13
    Figure US20140179670A1-20140626-C00467
    Figure US20140179670A1-20140626-C00468
         		4 1.60 (s, 1.5H), 1.65 (s, 1.5H), 3.28 (s, 1.5H), 3.30 (s, 1.5H), 6.39-6.42 (m, 1H), 7.23-7.36 (m, 2H), 7.39-7.45 (m, 0.5H), 7.47-7.54 (m, 2.5H), 7.65- 7.71 (m, 2H), 7.74-7.76 (m, 1H)
    14
    Figure US20140179670A1-20140626-C00469
    Figure US20140179670A1-20140626-C00470
         		4 1.57 (s, 3H), 3.30 (s, 3H), 6.41 (d, 1H, J = 1.8 Hz), 6.97-7.03 (m, 1H), 7.16-7.22 (m, 1H), 7.38-7.55 (m, 5H), 7.64-7.68 (m, 2H), 7.74 (d, 1H, J = 1.8 Hz)
    15
    Figure US20140179670A1-20140626-C00471
    Figure US20140179670A1-20140626-C00472
         		1 1.60 (s, 3H), 3.28 (s, 2H), 3.29 (s, 1H), 6.40 (d, 0.75H, J = 1.8 Hz), 6.41 (d, 0.25H, J = 1.8 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.48-7.53 (m, 2H), 7.58-7.79 (m, 6H)
    16
    Figure US20140179670A1-20140626-C00473
    Figure US20140179670A1-20140626-C00474
         		1 1.63 (s, 3H), 3.35 (s, 3H), 6.46 (d, 1H, J = 1.8 Hz), 7.39 (t, 1H, J = 1.8 Hz), 7.58 (d, 2H, J = 6.0 Hz), 7.71- 7.80 (m, 6H)
    17
    Figure US20140179670A1-20140626-C00475
    Figure US20140179670A1-20140626-C00476
         		1 1.65 (s, 1.5H), 1.68 (s, 1.5H), 3.33 (s, 1.5H), 3.34 (s, 1.5H), 6.45 (dd, 1H, J = 7.8, 1.8 Hz), 7.04 (d, 0.5H, J = 8.4 Hz), 7.19-7.22 (m, 0.5H), 7.27-7.35 (m, 1H) 7.38-7.43 (m, 1H), 7.54-7.64 (m, 3H), 7.70-7.73 (m, 2H), 7.79 (t, 1H, J = 1.5 Hz)
    18
    Figure US20140179670A1-20140626-C00477
    Figure US20140179670A1-20140626-C00478
         		1 1.62 (s, 1.5H), 1.68 (s, 1.5H), 3.28 (s, 1.5H), 3.30 (s, 1.5H), 6.39 (d, 0.5H, J = 1.7 Hz), 6.43 (d, 0.5H, J = 1.7 Hz), 7.40-7.43 (m, 0.5H), 7.50-7.60 (m, 2.5H), 7.65-7.76 (m, 4H), 8.01 (t, 0.5H, J = 2.1 Hz), 8.13 (t, 0.5H, J = 2.1 Hz), 8.30-8.34 (m, 1H)
    • Reference Example 206
  • In the preparation of Example 18, a purification by silica gel column chromatography (eluent: hexane/ethyl acetate) gave a regioisomer of the compound of Example 18, 4-[4-[3,6-dimethyl-1-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile.
  • Figure US20140179670A1-20140626-C00479
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.96 (s, 1.5H), 1.98 (s, 1.5H), 3.40 (s, 3H), 6.85 (d, 0.5H, J=3.0 Hz), 6.89 (d, 0.5H, J=3.0 Hz), 6.97-7.03 (m, 2H), 7.17-7.21 (m, 1H), 7.49-7.52 (m, 2H), 7.56-7.60 (m, 0.5H), 7.64-7.67 (m, 0.5H), 7.74 (d, 0.5H, J=8.8 Hz), 7.79 (d, 0.5H, J=8.8 Hz), 8.14 (t, 0.5H, J=2.1 Hz), 8.19 (t, 0.5H, J=2.1 Hz), 8.38-8.41 (m, 1H)
    • Examples 20-23
  • The compounds indicated in the below-mentioned table (Examples 20-33) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 1.
    • Example 20
  • 3,6-dimethyl-5-(1-phenyl-1H-pyrazol-5-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione
    • Example 21
  • 5-[1-(-chlorophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4 (H,3H)-dione
    • Example 22
  • 5-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione
    • Example 23
  • 5-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]picolinonitrile
  • Figure US20140179670A1-20140626-C00480
  • TABLE 37
    Measure-
    ment 1H-NMR (δ PPM)
    Ex. Ar2 cond. (or LC-MS: [M + H]+/Rt)
    20
    Figure US20140179670A1-20140626-C00481
         		1 1.40 (s, 1.5H), 1.44 (s, 1.5H), 3.32 (s, 3H), 6.40 (dd, 1H, J = 1.8, 0.9 Hz), 7.08 (d, 1H, J = 7.8 Hz), 7.27-7.41 (m, 5H), 7.48-7.60 (m, 2H), 7.67 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 1.8 Hz)
    21
    Figure US20140179670A1-20140626-C00482
         		1 1.51 (s, 1.5H), 1.52 (s, 1.5H), 3.30 (s, 1.5H), 3.31 (s, 1.5H), 6.39 (dd, 1H, J = 3.6, 2.1 Hz), 7.24-7.28 (m, 1H), 7.30-7.37 (m, 4H), 7.48 (s, 1H), 7.61 (d, 1H, J = 8.4 Hz), 7.68-7.71 (m, 2H)
    22
    Figure US20140179670A1-20140626-C00483
         		1 1.50 (s, 1.5H), 1.51 (s, 1.5H), 3.29 (s, 1.5H), 3.30 (s, 1.5H), 6.37 (dd, 1H, J = 3.3, 1.8 Hz), 6.77-7.09 (m, 4H), 7.28-7.33 (m, 1H), 7.37-7.48 (m, 1H), 7.54-7.69 (m, 3H)
    23
    Figure US20140179670A1-20140626-C00484
         		8 453 (MH+)/2.21 (min)
    • Examples 24-27
  • The compounds indicated in the below-mentioned table (Examples 24-27) were obtained by using the starting materials according to the similar reaction and treatment method to those described in Example 1.
    • Example 24
  • 5-(1-(5-bromopyridin-2-yl)-1H-pyrazol-5-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4 (1H, 3H)-dione
    • Example 25
  • 5-(5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)nicotinonitrile
    • Example 26
  • 4-(5-(3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 27
  • tert-butyl 2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propionate
  • Figure US20140179670A1-20140626-C00485
  • TABLE 38
    Measure-
    ment
    Ex. R1 R4 Ar2 cond. 1H-NMR (δ PPM)
    24
    Figure US20140179670A1-20140626-C00486
    Figure US20140179670A1-20140626-C00487
    Figure US20140179670A1-20140626-C00488
         		1 1.33 (d, 3H, J = 6.9 Hz), 1.37 (d, 3H, J = 6.9 Hz), 1.71 (s, 1.5H), 1.72 (s, 1.5H), 4.99- 5.09 (m, 1H), 6.34 (d, 0.5H, J = 3.7 Hz), 6.35 (d, 0.5H, J = 1.7 Hz), 7.45 (t, 1H, J = 8.3 Hz), 7.52 (s, 1H), 7.62 (t, 1H, J = 7.8 Hz), 7.68-7.71 (m, 2H), 7.83-7.85 (m, 2H), 8.23-8.24 (m, 0.5H), 8.27-8.28 (m, 0.5H)
    25
    Figure US20140179670A1-20140626-C00489
    Figure US20140179670A1-20140626-C00490
    Figure US20140179670A1-20140626-C00491
         		1 1.30 (dd, 3H, J = 7.0, 2.0 Hz), 1.37 (d, 3H, J = 6.8 Hz), 1.80 (s, 1.5H), 1.82 (s, 1.5H), 4.96-5.06 (m, 1H), 6.46 (d, 0.5H, J = 1.7 Hz), 6.48 (d, 0.5H, J = 1.7 Hz), 7.45-7.70 (m, 4H), 7.76-7.83 (m, 2H), 8.08-8.14 (m, 1H), 8.74 (d, 0.5H, J = 2.4 Hz), 8.78 (d, 0.5H, J = 2.4 Hz)
    26
    Figure US20140179670A1-20140626-C00492
         		H
    Figure US20140179670A1-20140626-C00493
         		1 1.35 (s, 9H), 1.45 (d, 3, J = 7.0 Hz), 5.29 (q, 1H, J = 7.0 Hz), 6.48 (d, 1H, J = 1.8 Hz), 7.44 (s, 1H), 7.48-7.54 (m, 2H), 7.56-7.62 (m, 3H), 7.65-7.70 (m, 4H)
    27
    Figure US20140179670A1-20140626-C00494
         		H
    Figure US20140179670A1-20140626-C00495
         		1 3.30 (s, 3H), 6.49 (d, 1H, J = 1.8 Hz), 7.39 (s, 1H), 7.46-7.48 (m, 2H), 7.55-7.62 (m, 3H), 7.66-7.70 (m, 4H)
    • Examples 28-29
  • The compounds indicated in the below-mentioned table (Examples 28-29) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 1.
    • Example 28
  • N′-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-1-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformimidamide
    • Example 29
  • N′-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3-(3-nitrophenyl)-2,6-dioxo-1-propyl-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformimidamide
  • Figure US20140179670A1-20140626-C00496
  • TABLE 39
    Measurement
    Ex. Ar1 R1 cond. 1H-NMR (δ PPM)
    28
    Figure US20140179670A1-20140626-C00497
    Figure US20140179670A1-20140626-C00498
         		1 2.20 (s, 3H), 2.63 (s, 3H), 3.35 (s, 3H), 6.47 (s, 1H), 6.75 (s, 1H), 7.13-7.17 (m, 1H), 7.25-7.35 (m, 1H), 7.45 (t, 1H, J = 7.8 Hz), 7.52-7.56 (m, 3H), 7.65-7.69 (m, 3H)
    29
    Figure US20140179670A1-20140626-C00499
    Figure US20140179670A1-20140626-C00500
         		1 0.85 (t, 3H, J = 7.4 Hz), 1.58-1.68 (m, 2H), 2.24 (brs, 3H), 2.65 (s, 3H), 3.88 (t, 2H, J = 7.4 Hz), 6.82 (s, 1H), 7.39-7.69 (m, 9H), 8.15 (dd, 1H, J = 9.2, 2.2 Hz)
    • Example 30
  • Tert-butyl 5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethyl)-2,3-dihydropyridine-1(6H)-yl]pentylcarbamate
  • Figure US20140179670A1-20140626-C00501
  • A solution of tert-butyl 5-[5-[3-[2-(4-cyanophenyl)hydrazono]prop-1-ynyl]-4-methyl-2,6-dihydro-3-(3-trifluorophenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentylcarbamate (prepared in Reference Example 163) (23.7 mg) in N,N-dimethy formamide (1.0 ml) was stirred at 120° C. for two hours and then at 150° C. for two hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford tert-butyl 5-[5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethyl)-2,3-dihydropyridine-1(6H)-yl]pentylcarbamate (14.1 mg).
  • 1H-NMR: the same as those of Example 8
    • Examples 31-40
  • The compounds indicated in the below-mentioned table (Examples 31-40) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 30.
    • Example 31
  • 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 32
  • 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]benzoic acid methyl ester
    • Example 33
  • 4-[5-[3,6-dimethyl-2,4-dioxo-1-(6-trifluoromethylpyridine-2-yl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 34
  • 4-[5-[1-(3-bromophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 35
  • 3-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
    • Example 36
  • 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]-3-(methylthio)benzonitrile
    • Example 37
  • 4-(5-(3,6-dimethyl-2,4-dioxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 38
  • 4-(5-(1-(3-tert-butylphenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 39
  • 4-(5-(3,6-dimethyl-1-(3-(methylsulfonyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 40
  • 5-(1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3,6-dimethyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione
  • Figure US20140179670A1-20140626-C00502
  • TABLE 40
    Measure-
    ment
    Ex. Ar1 Ar2 cond. 1H-NMR (δ PPM)
    31
    Figure US20140179670A1-20140626-C00503
    Figure US20140179670A1-20140626-C00504
         		1 those as the same as Ex. 1
    32
    Figure US20140179670A1-20140626-C00505
    Figure US20140179670A1-20140626-C00506
         		1 1.63 (s, 1.5H), 1.65 (s, 1.5H), 3.34 (s, 1.5H), 3.35 (s, 1.5H), 3.92 (s, 1.5H), 3.94 (s, 1.5H), 6.64 (dd, 1H, J = 5.1, 1.8 Hz), 7.27- 7.30 (m, 0.5H), 7.44-7.47 (m, 0.5H), 7.55- 7.64 (m, 3H), 7.70-7.76 (m, 2.5H), 7.79 (t, 1H, J = 2.1 Hz), 7.93 (t, 0.5H, J = 1.8 Hz), 8.17 (d, 1H, J = 7.8 Hz)
    33
    Figure US20140179670A1-20140626-C00507
    Figure US20140179670A1-20140626-C00508
         		1 1.66 (s, 3H), 3.28 (s, 3H), 6.43 (d, 1H, J = 1.5 Hz), 7.52-7.57 (m, 3H), 7.70 (d, 2H, J = 8.1 Hz), 7.75 (d, 1H, J = 1.5 Hz), 7.79 (d, 1H, J = 7.8 Hz), 8.07 (t, 1H, J = 8.1 Hz)
    34
    Figure US20140179670A1-20140626-C00509
    Figure US20140179670A1-20140626-C00510
         		1 1.64 (s, 1.5H), 1.68 (s, 1.5H), 3.32 (s, 1.5H), 3.34 (s, 1.5H), 6.45 (dd, 1H, J = 4.8, 1.8 Hz), 6.98 (dt, 0.5H, J = 7.2, 1.8 Hz), 7.12-7.17 (m, 1H), 7.27 (t, 0.5H, J = 1.5 Hz), 7.45-7.47 (m, 2H), 7.57-7.61 (d, 2H, J = 8.7, 1.5 Hz), 7.69- 7.72 (m, 2H), 7.79 (t, 1H, J = 1.5 Hz)
    35
    Figure US20140179670A1-20140626-C00511
    Figure US20140179670A1-20140626-C00512
         		1 1.61 (s, 1.5H), 1.63 (s, 1.5H), 3.29 (s, 3H), 6.40 (dd, 1H, J = 4.2, 1.8 Hz), 7.31 (d, 1H, J = 9.6 Hz), 7.50-7.54 (m, 1H), 7.59-7.74 (m, 7H)
    36
    Figure US20140179670A1-20140626-C00513
    Figure US20140179670A1-20140626-C00514
         		1 1.76 (d, 3H, J = 3.0 Hz), 2.36 (d, 3H, J = 4.2 Hz), 3.22 (s, 3H), 6.39 (d, 1H, J = 4.2 Hz), 7.25-7.33 (m, 1H), 7.39-7.46 (m, 4H), 7.59-7.62 (m, 1H), 7.71 (d, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 1.8 Hz)
  • TABLE 41
    Measure-
    ment
    Ex. Ar1 Ar2 cond. 1H-NMR (δ PPM)
    37
    Figure US20140179670A1-20140626-C00515
    Figure US20140179670A1-20140626-C00516
         		1 1.59 (d, 3H, J = 6.3 Hz), 2.33 (d, 3H, J = 2.7 Hz), 3.29 (d, 3H, J = 2.7 Hz), 6.40 (d, 1H, J = 2.2 Hz), 6.80 (d, 1H, J = 9.9 Hz), 6.98 (d, 1H, J = 9.9 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.33 (q, 1H, J = 7.5 Hz), 7.50-7.54 (m, 2H), 7.64- 7.68 (m, 2H), 7.74 (d, 1H, J = 1.8 Hz)
    38
    Figure US20140179670A1-20140626-C00517
    Figure US20140179670A1-20140626-C00518
         		1 1.23 (s, 4.5H), 1.26 (s, 4.5H), 1.50 (s, 1.5H), 1.56 (s, 1.5H), 3.30 (d, 3H, J = 3.9 Hz), 6.42 (d, 1H, J = 1.8 Hz), 6.81 (ddd, 0.5H, J = 7.8, 2.1, 1.2 Hz), 6.86 (t, 0.5H, J = 2.1 Hz), 6.99 (ddd, 0.5H, J = 7.5, 2.1, 1.2 Hz), 7.16 (t, 0.5H, J = 2.1 Hz), 7.33-7.35 (m, 2H), 7.52 (t, 2H, J = 6.6 Hz), 7.67 (t, 2H, J = 7.8 Hz), 7.74 (dd, 1H, J = 1.8, 0.9 Hz)
    39
    Figure US20140179670A1-20140626-C00519
    Figure US20140179670A1-20140626-C00520
         		1 1.59 (s, 1H), 1.67 (s, 1H), 1.80 (d, 1H, J = 0.9 Hz), 3.10 (d, 3H, J = 2.1 Hz), 3.30 (d, 3H, J = 1.2 Hz), 6.38 (d, 0.5H, J = 1.8 Hz), 6.42 (d, 0.5H, J = 1.5 Hz), 7.34-7.42 (m, 1H), 7.46-7.83 (m, 6H), 7.79 (t, 0.5H, J = 1.8 Hz), 7.83 (t, 0.5H, J = 1.8 Hz), 8.00-8.03 (m, 1H)
    40
    Figure US20140179670A1-20140626-C00521
    Figure US20140179670A1-20140626-C00522
         		1 1.44 (s, 1.5H), 1.47 (s, 1.5H), 3.31 (s, 3H), 3.78 (s, 3H), 6.36 (dd, 1H, J = 1.8 Hz), 6.60- 7.01(m, 5H), 7.29 (d, 1H, J = 9.0 Hz), 7.38- 7.66 (m, 2H), 7.70 (d, 1H, J = 2.1 Hz)
    • Examples 41-49
  • The compounds indicated in the below-mentioned table (Examples 41-49) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 30.
    • Example 41
  • 4-(5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 42
  • 4-(5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 43
  • 4-(5-(3-cyclopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 44
  • 4-(5-(3-cyclobutyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 45
  • benzyl 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)azetidine-1-carboxylate
    • Example 46
  • (S)-ethyl 2-(5-(1-(4-bromophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propanoate
    • Example 47
  • acetic acid (R)-2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propyl ester
    • Example 48
  • (S)-4-(5-(6-methyl-2,4-dioxo-3-(1-phenylethyl)-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 49
  • acetic acid 2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)ethyl ester
  • Figure US20140179670A1-20140626-C00523
  • TABLE 42
    Measure-
    ment
    Ex. Ar1 Ar2 R1 cond. 1H-NMR (δ PPM)
    41
    Figure US20140179670A1-20140626-C00524
    Figure US20140179670A1-20140626-C00525
         		Et 1 1.17 (t, 3H, J = 6.9 Hz), 1.66 (s, 1.5H), 1.71 (s, 1.5H), 3.91-4.00 (m, 2H), 6.45 (d, 0.5H, J = 1.8 Hz), 6.76 (d, 0.5H, J = 2.1 Hz), 7.33 (d, 1H, J = 8.1H), 7.41 (s, 0.5H), 7.47 (d, 0.5H, J = 8.1 Hz), 7.55-7.59 (m, 2H), 7.63-7.67 (m, 1H), 7.70-7.75 (m, 3H), 7.79 (t, 1H, J = 1.5 Hz)
    42
    Figure US20140179670A1-20140626-C00526
    Figure US20140179670A1-20140626-C00527
         		iPr 1 1.28-1.37 (m, 6H), 1.61 (brs, 2H), 1.65 (brs, 1H), 5.02 (sept, 1H, J = 6.9 Hz), 6.40 (dd, 1H, J = 8.1, 1.8 Hz), 7.33 (d, 1H, J = 8.1 Hz), 7.41 (d, 1H, J = 1/1.7 Hz), 7.50-7.57 (m, 2H), 7.60-7.71 (m, 4H), 7.73 (t, 1H, J = 1.5 Hz)
    43
    Figure US20140179670A1-20140626-C00528
    Figure US20140179670A1-20140626-C00529
         		cPr 1 0.45-0.60 (m, 1H), 0.74-0.76 (m, 1H), 0.99-1.07 (m, 2H), 1.61 (s, 1.5H), 1.66 (s, 1.5H), 2.58-2.67 (m, 1H), 6.39 (dd, 1H, J = 6.3, 1.8 Hz), 7.27 (d, 0.5H, J = 7.8 Hz), 7.36 (s, 0.5H), 7.40 (d, 0.5H, J = 7.8 Hz), 7.50-7.54 (m, 2.5H), 7.58-7.74 (m, 5H)
    44
    Figure US20140179670A1-20140626-C00530
    Figure US20140179670A1-20140626-C00531
    Figure US20140179670A1-20140626-C00532
         		1 1.62 (s, 1.5H), 1.67 (s, 1.5H), 1.70- 1.85 (m, 2H), 2.14-2.26 (m, 2H), 2.65-2.82 (m, 2H), 5.09-5.17 (m, 1H), 6.44 (dd, 1H, J = 7.2, 1.8 Hz), 7.32 (d, 0.5H, J = 7.2 Hz), 7.40 (s, 0.5H), 7.46 (d, 0.5H, J = 8.1 Hz), 7.54- 7.60 (m, 2.5H), 7.63-7.76 (m, 4H), 7.79 (t, 1H, J = 1.8 Hz)
  • TABLE 43
    Measure-
    ment
    Ex. Ar1 Ar2 R1 cond. 1H-NMR (δ PPM)
    45
    Figure US20140179670A1-20140626-C00533
    Figure US20140179670A1-20140626-C00534
    Figure US20140179670A1-20140626-C00535
         		1 1.60 (s, 1.5H), 1.64 (s, 1.5H), 4.14-4.19 (m, 2H), 4.23-4.35 (m, 2H), 5.00 (d, 2H, J = 2.1 Hz), 5.19-5.27 (m, 1H), 6.40 (dd, 1H, J = 6.0, 1.8 Hz), 7.22-7.27 (m, 6H), 7.33 (s, 0.5H), 7.41 (d, 0.5H, J = 7.5 Hz), 7.48-7.51 (m, 2H), 7.59-7.75 (m, 5H)
    46
    Figure US20140179670A1-20140626-C00536
    Figure US20140179670A1-20140626-C00537
    Figure US20140179670A1-20140626-C00538
         		1 1.15-1.20 (m, 3H), 1.47-1.55 (m, 6H), 4.05- 4.18 (m, 2H), 5.35-5.46 (m, 1H), 6.39-6.42 (m, 1H), 7.21-7.27 (m, 3H), 7.38-7.61 (m, 4H), 7.67-7.69 (m, 2H)
    47
    Figure US20140179670A1-20140626-C00539
    Figure US20140179670A1-20140626-C00540
    Figure US20140179670A1-20140626-C00541
         		1 1.36-1.48 (m, 3H), 1.63 (dd, 3H, J = 13.5, 3.0 Hz), 1.95-2.02 (m, 3H), 4.06-4.27 (m, 1H), 4.54-4.71 (m, 1H), 5.15 (brs, 1H), 6.43 (d, 0.25H, J = 1.8 Hz), 6.46 (t, 0.5H, J = 1.8 Hz), 6.49 (d, 0.25H, J = 1.8 Hz), 7.27-7.36 (m, 1H), 7.41-7.50 (m, 1H), 7.57-7.79 (m, 7H)
    48
    Figure US20140179670A1-20140626-C00542
    Figure US20140179670A1-20140626-C00543
    Figure US20140179670A1-20140626-C00544
         		4 1.56-1.59 (m, 1.5H), 1.65-1.69 (m, 1.5H), 1.83 (d, 1.5H, J = 3.6 Hz), 1.89 (d, 1.5H, J = 4.5 Hz), 5.90 (q, 1H, J = 6.9 Hz), 6.57 (d, 0.5H, J = 2.7 Hz), 6.57 (d, 0.5H, J = 3.2 Hz), 7.05-7.09 (m, 1H), 7.12-7.17 (m, 1H), 7.19- 7.29 (m, 3H), 7.62-7.69 (m, 1H), 7.73-8.10 (m, 8H)
    49
    Figure US20140179670A1-20140626-C00545
    Figure US20140179670A1-20140626-C00546
    Figure US20140179670A1-20140626-C00547
         		3 1.57 (s, 1.5H), 1.59 (s, 1.5H), 1.94 (s, 1.5H), 1.95 (s, 1.5H), 4.09-4.14 (m, 1H), 4.18-4.24 (m, 2H), 4.37-4.46 (m, 1H), 6.45 (d, 0.5H, J = 1.5Hz), 6.48 (d, 0.5H, J = 9.6 Hz), 7.28 (d, 0.5H, J = 9.6 Hz), 7.37 (s, 0.5H), 7.47 (d, 0.5H, J = 7.5 Hz), 7.54 (s, 0.5H), 7.63- 7.68 (m, 3H), 7.72-7.76 (m, 3H), 7.80 (t, 1H, J = 1.8 Hz)
    • Examples 50-56
  • The compounds indicated in the below-mentioned table (Examples 50-56) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 30.
    • Example 50
  • 4-(5-(6-ethyl-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 51
  • 4-(5-(6-isopropyl-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 52
  • 4-(5-(6-(dimethylamino)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 53
  • 4-(5-(2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 54
  • 4-(5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 55
  • (R)-4-(5-(3-(1-hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 56
  • 4-(5-(3-isopropyl-1-(2-methyl-5-(trifluoromethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00548
  • TABLE 44
    Measure-
    ment
    Ex. Ar1 Ar2 R1 R4 cond. 1H-NMR (δ PPM)
    50
    Figure US20140179670A1-20140626-C00549
    Figure US20140179670A1-20140626-C00550
         		Me Et 4 0.68 (t, 1.5H, J = 7.6 Hz), 0.70 (t, 1.5H, J = 7.5 Hz), 1.98-2.07 (m, 1H), 2.09-2.19 (m, 1H), 3.37 (s, 1.5H), 3.38 (s, 1.5H), 6.49 (d, 0.5H, J = 7.2 Hz), 6.50 (d, 0.5H, J = 7.2 Hz), 7.33-7.36 (m, 0.5H), 7.39 (s, 0.5H), 7.55-7.58 (m, 0.5H), 7.63-7.70 (m, 3H), 7.70-7.80 (m, 3.5H), 7.82-7.84 (m, 1H)
    51
    Figure US20140179670A1-20140626-C00551
    Figure US20140179670A1-20140626-C00552
         		Me iPr 4 0.57 (t, 3H, J = 7.8 Hz), 0.88 (t, 3H, J = 7.0 Hz), 2.50-2.58 (m, 1H), 3.39 (s, 1.5H), 3.40 (s, 1.5H), 6.47 (d, 0.5H, 4.3 Hz), 6.48 (d, 0.5H, J = 4.3 Hz), 7.35- 7.40 (m, 0.5H), 7.44 (s, 0.5H), 7.52-7.60 (m, 0.5H), 7.64 (s, 0.5H), 7.66-7.68 (m, 3H), 7.70- 7.82 (m, 3H), 7.82-7.83 (m, 1H)
    52
    Figure US20140179670A1-20140626-C00553
    Figure US20140179670A1-20140626-C00554
         		Me NMe2 4 1.88 (s, 6H), 3.41 (s, 3H), 6.51 (s, 1H), 7.44-7.66 (m, 2H), 7.61 (t, 1H, J = 8.0 Hz), 7.66 (d, 1H, J = 8.1 Hz), 7.70-7.77 (m, 4H), 7.81-7.84 (m, 1H)
  • TABLE 45
    Measure-
    ment
    Ex. Ar1 Ar2 R1 R4 cond. 1H-NMR (δ PPM)
    53
    Figure US20140179670A1-20140626-C00555
    Figure US20140179670A1-20140626-C00556
         		H H 4 6.59 (d, 1H, J = 1.8 Hz), 7.49 (s, 1H), 7.56 (s, 1H), 7.56 (d, 1H, J = 8.0 Hz), 7.62-7.70 (m, 3H), 7.74-7.79 (m, 4H), 8.31 (s, 1H)
    54
    Figure US20140179670A1-20140626-C00557
    Figure US20140179670A1-20140626-C00558
         		iPr H 1 1.37 (d, 6H, J = 6.9 Hz), 5.08 (quin, 1H, J = 6.9 Hz), 6.51 (d, 1H, J = 1.5 Hz), 7.46 (s, 1H), 7.55-7.67 (m, 5H), 7.71-7.74 (m, 4H)
    55
    Figure US20140179670A1-20140626-C00559
    Figure US20140179670A1-20140626-C00560
    Figure US20140179670A1-20140626-C00561
         		Me 1 1.30-1.37 (m, 3H), 1.66 (d, 1.5H, J = 1.8 Hz), 1.70 (d, 1.5H, J = 1.8 Hz), 3.71-3.81 (m, 1H), 3.92-4.00 (m, 1H), 5.10 (brs, 1H). 6.43-6.45 (m, 1H), 7.26-7.30 (m, 1H), 7.49- 7.59 (m, 3H), 7.64-7.80 (m, 5H)
    56
    Figure US20140179670A1-20140626-C00562
    Figure US20140179670A1-20140626-C00563
         		iPr H 4 1.41 (d, 6H, J = 6.9 Hz), 2.26 (s, 3H), 5.12 (sept, 1H, J = 6.9 Hz), 6.53 (d, 1H, J = 1.8 Hz), 7.29 (s, 1H), 7.47 (s, 1H), 7.50 (d, 1H, J = 8.1 Hz), 7.61-7.67 (m, 3H), 7.72-7.77 (m, 3H)
    • Example 57
  • 4-[5-[6-Amino-1-(3-nitrophenyl)-2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00564
  • To a solution of N′-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3-(3-nitrophenyl)-2,6-dioxo-1-propyl-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformimidamide (prepared in Example 29) (11.0 mg) in ethanol (1.0 ml) was added 1N hydrochloric acid (2.0 ml) and the resulting mixture was stirred with heating under reflux for six hours. The reaction mixture was concentrated under reduced pressure, and weakly basified with aqueous sodium hydroxide solution, and thereto was added water and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[5-[6-amino-1-(3-nitrophenyl)-2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (7.0 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 0.77 (t, 1.5H, J=7.4 Hz), 0.79 (t, 1.5H, J=7.4 Hz), 1.48-1.52 (m, 2H), 3.64-3.82 (m, 2H), 4.37 (s, 1H), 4.41 (s, 1H), 6.47 (d, 1H, J=9.4 Hz), 7.38-7.76 (m, 7H), 8.18 (brs, 0.5H), 8.25 (brs, 0.5H), 8.37 (brd, 1H, J=7.9 Hz)
    • Example 58
  • 4-[5-[6-Amino-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00565
  • The above-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 57.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 3.21 (s, 1.5H), 3.22 (s, 1.5H), 4.27 (s, 1H), 4.32 (s, 1H), 6.47 (d, 1H, J=5.3 Hz), 7.43-7.81 (m, 9H)
    • Example 59
  • 4-(3-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)pyridin-2-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00566
  • 5-(2-Bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 189) (132 mg) and 4-cyanophenylboronic acid (166 mg) were dissolved in 1,4-dioxane (10 ml). Thereto were added under nitrogen atmosphere water (1 ml), sodium carbonate (239 mg) and tetrakis(triphenylphosphine)palladium (33 mg) and the resulting mixture was stirred with heating under reflux for one and a half hours. The reaction mixture was cooled to room temperature, and thereto was then water and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: firstly hexane/ethyl acetate, secondly chloroform/methanol) to afford 4-(3-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)pyridin-2-yl)benzonitrile (118 mg).
  • 1H-NMR (400 MHz, DMSO-d6) (δ PPM):
  • 1.13 (d, 3H, J=6.9 Hz), 1.24 (dd, 3H, J=4.8, 6.8 Hz), 1.56 (s, 1.5H), 1.60 (s, 1.5H), 4.78-4.88 (m, 1H), 7.50-7.56 (m, 1H), 7.60-7.67 (m, 2.5H), 7.75 (s, 0.5H), 7.78-7.83 (m, 2.5H), 7.87-7.91 (m, 3H), 7.94 (s, 0.5H), 8.71 (dd, 1H, J=0.6, 4.7 Hz)
    • Examples 60-61
  • The compounds indicated in the below-mentioned table (Examples 60-61) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 59.
    • Example 60
  • 2-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]biphenyl-4-carbonitrile
    • Example 61
  • 4-[3-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-pyridin-2-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00567
  • TABLE 46
    Measure-
    ment
    Ex. L—Ar2 R1 cond. 1H-NMR (δ PPM)
    60
    Figure US20140179670A1-20140626-C00568
    Figure US20140179670A1-20140626-C00569
         		4 1.39 (s, 1.5H), 1.40 (s, 1.5H), 3.38 (s, 1.5H), 3.39 (s, 1.5H), 6.98 (s, 1H), 7.34-7.41 (m, 4H), 7.45-7.53 (m, 3H), 7.58-7.70 (m, 4H)
    61
    Figure US20140179670A1-20140626-C00570
    Figure US20140179670A1-20140626-C00571
         		1 1.29 (s, 1.5H), 1.31 (s, 1.5H), 3.35 (s, 1.5H), 3.36 (s, 1.5H), 6.95 (brs, 1H), 7.35-7.39 (m, 2H), 7.46 (brs, 0.5H), 7.52-7.61 (m, 3H), 7.64-7.69 (m, 4H), 8.69 (d, 1H, J = 5.0 Hz)
    • Example 62
  • 4-[4-[6-Methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-4H-1,2,4-triazol-3-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00572
  • A solution of 4-cyanobenzohydrazide (46.0 mg) and dimethylformamide dimethylacetal (110 μl) in N,N-dimethy formamide (2.0 ml) was stirred at 50° C. for thirty minutes and then cooled to room temperature, and thereto were added 5-amino-6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 193) (20.0 mg) and acetic acid (0.5 ml) and the resulting mixture was stirred at 130° C. for eight hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[4-[6-methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-4H-1,2,4-triazol-3-yl]benzonitrile (7.8 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 0.95 (t, 3H, J=8.5 Hz), 1.59 (s, 1.5H), 1.62 (s, 1.5H), 1.66-1.74 (m, 2H), 3.93-4.00 (m, 2H), 7.30 (d, 0.5H, J=6.0 Hz), 7.38 (s, 0.5H), 7.49 (d, 0.5H, J=6.0 Hz), 7.59 (s, 0.5H), 7.66-7.82 (m, 5H), 8.26 (d, 1H, J=5.5 Hz)
    • Examples 63-64
  • The compound indicated in the below-mentioned table (Examples 63-64) were prepared by using the starting materials according to the similar reaction and treatment method to those described in Example 62.
    • Example 63
  • 4-(4-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-5-methyl-4H-1,2,4-triazol-3-yl)benzonitrile
    • Example 64
  • 4-(4-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00573
  • TABLE 47
    Measure-
    ment
    Ex. R1 R4 R5 cond. 1H-NMR (δ PPM)
    63 iPr H
    Figure US20140179670A1-20140626-C00574
         		4 1.51 (d, 3H, J = 6.8 Hz), 1.52 (d, 3H, J = 6.8 Hz), 2.45 (s, 3H), 5.22 (sept, 1H, J = 6.9 Hz), 7.49 (d, 1H, J = 7.9 Hz), 7.54 (s, 1H), 7.64-7.70 (m, 4H), 7.73-7.77 (m, 3H)
    64 iPr H H 1 1.47 (d, 6H, J = 7.0 Hz), 5.13-5.23
    (m, 1H), 7.48-7.55 (m, 3H), 7.65
    (t, 1H, J = 7.5 Hz), 7.72 (s, 1H),
    7.75-7.78 (m, 4H), 8.30 (s, 1H)
    • Example 65
  • 4-(4-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00575
  • To a solution of 3-isopropyl-6-methyl-5-nitro-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 195) (1.68 g) in ethyl acetate/methanol (20.0 ml/20.0 ml) was added palladium hydroxide (500.0 mg) and the resulting mixture was performed catalytic hydrogenation at room temperature for four and a half hours. The reaction mixture was degassed and then filtered through Celite (trade mark) and then concentrated under reduced pressure to afford the residue (897.0 mg) containing 5-amino-3-isopropyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione. A solution of the resulting residue (150.0 mg), dimethylformamide dimethylacetal (340 μl) and acetic acid (7 μl) in N,N-dimethy formamide (4.0 ml) was stirred at 110° C. for forty-five minutes and then cooled to room temperature, and thereto were added 4-cyanobenzohydrazide (221.4 mg) and acetic acid (690 μl) and the resulting mixture was stirred at 130° C. for two hours. To the reaction mixture was added water (30 ml) and the resulting mixture was extracted with ethyl acetate (30 ml×2). The organic layer was washed with water (30 ml×2) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) and aminosilica gel column chromatography (eluent: ethyl acetate/methanol) to afford 4-(4-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile (64.1 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.39-1.43 (m, 6H), 1.50 (s, 1.5H), 1.52 (s, 1.5H), 5.40-5.16 (m, 1H), 7.25 (d, 0.5H, J=7.7 Hz), 7.32 (s, 0.5H), 7.43 (d, 0.5H, J=7.7 Hz), 7.52 (s, 0.5H), 7.59-7.72 (m, 6H), 8.25 (brs, 1H)
    • Example 66
  • 4-(4-(3,6-Dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00576
  • The intended product was obtained by using the corresponding starting materials according to the similar reaction and treatment method described in Example 62.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.52 (s, 1.5H), 1.55 (s, 1.5H), 3.37 (s, 1.5H), 3.39 (s, 1.5H), 7.23 (s, 0.5H), 7.30 (s, 0.5H), 7.42-7.65 (m, 0.5H), 7.52 (brs, 0.5H), 7.60-7.65 (m, 1H), 7.72-7.76 (m, 5H), 8.23 (brs, 1H)
    • Example 67
  • 5-(3-(5-Bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione
  • Figure US20140179670A1-20140626-C00577
  • The intended product was obtained by using the corresponding starting materials according to the similar reaction and treatment method described in Example 65.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.43-1.47 (m, 6H), 1.68 (s, 3H), 5.09-5.18 (m, 1H), 7.47-7.53 (m, 1.5H), 7.61 (s, 0.5H), 7.70 (t, 1H, J=8.0 Hz), 7.78 (d, 1H, J=7.7 Hz), 7.94-7.97 (m, 1H), 8.20 (d, 1H, J=3.5 Hz), 8.30 (d, 1H, J=8.6 Hz), 8.56 (dd, 1H, J=8.8, 2.2 Hz)
    • Example 68
  • 4-[5-[6-Methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00578
  • To a solution of 4-[5-[3-(2,2-dimethoxyethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 7) (10.0 mg) in tetrahydrofuran (0.5 ml)/water (0.1 mL) was added trifluoroacetic acid (40 μl) and the resulting mixture was stirred at 100° C. for three hours. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and thereto was added water and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 4-[5-[6-methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (9.1 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.60 (s, 1.5H), 1.65 (s, 1.5H), 4.76-4.88 (m, 2H), 6.42 (d, 0.5H, J=6.2 Hz), 6.43 (d, 0.5H, J=6.2 Hz), 7.28 (d, 0.5H, J=9.6 Hz), 7.38 (s, 0.5H), 7.43 (d, 0.5H, J=9.6 Hz), 7.50 (s, 0.5H), 7.52-7.56 (m, 3H), 7.69-7.75 (m, 4H), 9.53 (s, 0.5H), 9.55 (s, 0.5H)
    • Example 69
  • 4-[5-[3-(2-Dimethylaminoethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00579
  • To a solution of 4-[5-[6-methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 68) (12.8 mg), dimethyl amine (133 μl) and acetic acid (10 μl) in tetrahydrofuran (1.0 ml) was added sodium triacetoxyborohydride (8.5 mg) and the resulting mixture was stirred at room temperature for four hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[5-[3-(2-dimethylaminoethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (7.4 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.64 (s, 1.5H), 1.68 (s, 1.5H), 2.23 (s, 6H), 2.42-2.48 (m, 2H), 4.03-4.07 (m, 2H), 6.46 (d, 1H, J=5.1 Hz), 7.30-7.79 (m, 9H)
    • Example 70
  • 4-[5-[6-Methyl-3-(2-methylaminoethyl)-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00580
  • The above-mentioned compound was prepared by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 69.
  • 1H-NMR (CD3OD: 300 MHz) (δ PPM):
  • 1.63 (brs, 3H), 1.69-1.75 (m, 3H), 2.18-2.24 (m, 1H), 2.40-2.54 (m, 1H), 3.96-4.00 (m, 1H), 4.02-4.08 (m, 1H), 6.42-6.46 (m, 1H), 7.47-7.79 (m, 9H)
    • Example 71
  • N-[2-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]ethyl]acetamide
  • Figure US20140179670A1-20140626-C00581
  • To a solution of 4-[5-[6-methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 68) (18.0 mg), ammonia (0.4 ml: 0.5 N tetrahydrofuran solution) and acetic acid (4 μl) in tetrahydrofuran (1.0 ml) was added sodium triacetoxyborohydride (11.9 mg) and the resulting mixture was stirred at room temperature for two hours. To the reaction mixture were added diisopropylethyl amine (48 μl) and acetic anhydride (78 μl) and the resulting mixture was stirred at 55° C. for two hours. To the reaction mixture was added water (20 ml) and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-[2-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]ethyl]acetamide (7.6 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.54 (s, 1.5H), 1.59 (s, 1.5H), 1.89 (s, 1.5H), 1.90 (s, 1.5H), 4.10-4.20 (m, 4H), 4.34-4.40 (m, 1H), 6.41 (d, 0.5H, J=7.5 Hz), 6.42 (d, 0.5H, J=7.5 Hz), 7.23 (d, 0.5H, J=6.1 Hz), 7.32 (s, 0.5H), 7.42 (d, 0.5H, J=6.1 Hz), 7.50 (s, 0.5H), 7.57-7.75 (m, 7H)
    • Example 72
  • 2-[5-[1-(4-Cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]acetic acid
  • Figure US20140179670A1-20140626-C00582
  • To a solution of 2-(5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]acetic acid benzyl ester (prepared in Example 6) (50.0 mg) in ethyl acetate (3.0 ml)/methanol (3.0 ml) was added 5% palladium/carbon (9.0 mg) and the resulting mixture was stirred at room temperature under hydrogen atmosphere for six hours. The reaction mixture was degassed and then filtered through Celite (trade mark) and then concentrated under reduced pressure to afford 2-[5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]acetic acid (47.0 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.74 (s, 1.5H), 1.77 (s, 1.5H), 4.53 (d, 2H, J=4.2 Hz), 6.59 (d, 0.5H, J=4.0 Hz), 6.60 (d, 0.5H, J=4.00 Hz), 7.76-7.85 (m, 9H).
    • Example 73
  • 3-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid
  • Figure US20140179670A1-20140626-C00583
  • A solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid ethyl ester (prepared in Example 4) (351.0 mg) in methanol (1.0 ml) was cooled under ice-cooling and thereto was added 2N aqueous sodium hydroxide solution (340 μl) and the resulting mixture was stirred at room temperature for twelve hours. The reaction mixture was diluted with diethylether (30 ml) and thereto was added water (30 ml). The organic layer and the aqueous layer were separated and the aqueous layer was then acidified with sodium hydrogen sulfate (500 mg) and extracted with ethyl acetate (50 ml×3). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained amorphous was washed with hexane (30 ml) to afford 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (239.5 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.60 (s, 1.5H), 1.64 (s, 1.5H), 2.64 (q, 2H, J=6.0 Hz), 4.25 (t, 2H, J=6.0 Hz), 6.46 (dd, 1H, J=6.0, 3.0 Hz), 7.26-7.31 (m, 1.5H), 7.38 (s, 0.5H), 7.44-7.53 (m, 1H), 7.55-7.66 (m, 2H), 7.68-7.75 (m, 3H), 7.79 (t, 1H, J=1.8 Hz)
    • Example 74
  • 4-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]butanoic acid
  • Figure US20140179670A1-20140626-C00584
  • The above-mentioned compound was prepared by using 4-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]butanoic acid ethyl ester (prepared in Example 5) according to the similar reaction and treatment method to those described in the Example 73.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.55 (s, 0.75H), 1.57 (s, 0.75H), 1.66 (s, 0.75H), 1.70 (s, 0.75H), 1.89-1.97 (m, 2H), 2.31 (brs, 2H), 3.96-4.04 (m, 2H), 6.44 (d, 0.25H, J=11.8 Hz), 6.46 (d, 0.75H, J=1.5 Hz), 7.30-7.86 (m, 8H), 8.11 (dd, 1H, J=6.9, 5.7 Hz)
    • Example 75
  • 3-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N,N-dimethylpropaneamide
  • Figure US20140179670A1-20140626-C00585
  • A solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (prepared in Example 73) (26.4 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (13.8 mg), 1-hydroxy-7-azabenzotriazole (15.9 mg) and N,N-diisopropylethylamine (0.1 ml) in tetrahydrofuran (0.5 ml) was cooled under ice-cooling and thereto was added dimethylamine (0.05 ml: 2M tetrahydrofuran solution) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was 1M aqueous potassium hydrogen sulfate solution (20 ml) and the resulting mixture was then extracted with ethyl acetate (20 ml×2). The organic layer was washed with water (10 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-[5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N,N-dimethylpropaneamide (3.1 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.64 (s, 3H), 2.62 (m, 2H), 2.86 (s, 3H), 2.99 (s, 1.5H), 3.01 (s, 1.5H), 4.21-4.26 (m, 2H), 6.47 (dd, 1H, J=6.0, 3.0 Hz), 7.38-7.55 (m, 4H), 7.64 (d, 1H, J=2.4 Hz), 7.67 (d, 1H, J=2.7 Hz), 7.73-7.79 (m, 3H)
    • Examples 76-82
  • The compounds indicated in the below-mentioned table (Examples 76-82) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 75.
    • Example 76
  • 2-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-acetamide
    • Example 77
  • 2-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N-methylacetamide
    • Example 78
  • 2-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N,N-dimethylacetamide
    • Example 79
  • 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N-methylpropaneamide
    • Example 80
  • 4-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N-methylbutaneamide
    • Example 81
  • 4-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]-N,N-dimethylbutaneamide
    • Example 82
  • (S)-2-(5-(1-(4-cyanophenyl)-1H-pyrazole-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)-N-(1-phenylethyl)acetamide
  • Figure US20140179670A1-20140626-C00586
  • TABLE 48
    Measure-
    ment
    Ex. p R1 cond. 1H-NMR (δ PPM)
    76 1
    Figure US20140179670A1-20140626-C00587
         		1 1.56 (s, 1.5H), 1.61 (s, 1.5H), 4.53-4.65 (m, 2H), 5.51 (brs, 2H), 6.43 (d, 0.5H, J = 6.3 Hz), 6.44 (d, 0.5H, J = 6.3 Hz), 7.30 (d, 0.5H, J = 7.9 Hz), 7.38 (s, 0.5H), 7.43 (d, 0.5H, J = 7.9 Hz), 7.50 (s, 0.5H), 7.53-7.63 (m, 3H), 7.67- 7.75 (m, 4H)
    77 1
    Figure US20140179670A1-20140626-C00588
         		1 1.61 (s, 1.5H), 1.66 (s, 1.5H), 2.82 (brs, 3H), 4.54 (d, 1H, J = 1/1.2 Hz), 4.57 (d, 1H, J = 1/1.2 Hz), 5.55 (brs, 1H), 6.47 (d, 0.5H, J = 6.5 Hz), 6.48 (d, 0.5H, J = 6.5 Hz), 7.30 (d, 0.5H, J = 6.8 Hz), 7.42 (s, 0.5H), 7.46 (d, 0.5H, J = 6.8 Hz), 7.54 (s, 0.5H), 7.58-7.63 (m, 3H), 7.72-7.79 (m, 4H)
    78 1
    Figure US20140179670A1-20140626-C00589
         		1 1.55 (s, 1.5H), 1.61 (s, 1.5H), 2.90 (s, 1.5H), 2.91 (s, 1.5H), 2.97 (s, 1.5H), 2.98 (s, 1.5H), 4.65 (d, 1H, J = 15.1 Hz). 4.75 (d, 1H, J = 15.1 Hz), 6.43 (d, 0.5H, J = 6.3 Hz), 6.44 (d, 0.5H, J = 6.3 Hz), 7.30 (d, 0.5H, J = 8.2 Hz), 7.39 (s, 0.5H), 7.42 (d, 0.5H, J = 8.2 Hz), 7.50 (s, 0.5H), 7.57-7.60 (m, 3H), 7.66-7.74 (m, 4H)
    79 2
    Figure US20140179670A1-20140626-C00590
         		1 1.65 (s, 3H), 2.45-2.53 (m, 2H), 2.73 (d, 3H, J = 3.0 Hz), 4.23 (m, 2H), 6.47 (dd, 1H, J = 6.0, 3.0 Hz), 7.45-7.54 (m, 2H), 7.59-7.68 (m, 3H), 7.71-7.80 (m, 4H)
    80 3
    Figure US20140179670A1-20140626-C00591
         		1 1.61 (s, 0.75H), 1.63 (s, 0.75H), 1.66 (s, 0.75H), 1.69 (s, 0.75H), 1.92-1.97 (m, 2H), 2.13-2.16 (m, 2H), 2.74-2.77 (m, 3H), 3.95-3.97 (m, 2H), 6.44-6.47 (m, 1H), 7.43-7.79 (m, 8H), 8.11 (t, 1H, J = 9.0 Hz)
    81 3
    Figure US20140179670A1-20140626-C00592
         		1 1.46 (s, 0.75H), 1.48 (s, 0.75H), 1.57 (s, 0.75H), 1.61 (s, 0.75H), 1.83-2.02 (m, 2H), 2.25-2.28 (m, 2H), 2.86-2.88 (m, 6H), 3.95 (t, 2H, J = 7.2 Hz), 6.39-6.42 (m, 1H), 7.46- 7.51 (m, 2H), 7.58-7.71 (m, 5H), 7.73-7.75 (m, 1H), 8.06 (t, 1 H, J = 7.8 Hz)
    82 1
    Figure US20140179670A1-20140626-C00593
         		1 1.38-1.41 (m, 3H), 1.50 (s, 0.5H), 1.55 (s, 0.5H), 1.56 (s, 0.5H), 1.60 (s, 0.5H), 4.52-4.55 (m, 2H), 4.97-5.04 (m, 1H), 5.86-5.95 (m, 1H), 6.40-6.43 (m, 1H), 7.16-7.31 (m, 6H), 7.39 (s, 1H), 7.47-7.50 (m, 2H), 7.55-7.58 (m, 2H), 7.66-7.74 (m, 3H)
    • Example 83
  • 4-[5-[3-(3-Hydroxypropyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00594
  • To a solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (prepared in Example 73) (36.2 mg) in tetrahydrofuran (0.5 ml) was added under ice-cooling borane tetrahydrofuran complex (0.1 ml:1.09 M tetrahydrofuran solution), and the resulting mixture was stirred at room temperature for eighteen hours. The reaction mixture was cooled again under ice-cooling and thereto was added borane tetrahydrofuran complex (0.2 ml:1.09 M tetrahydrofuran solution) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (2 ml) and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[5-[3-(3-hydroxypropyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (26.2 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.66 (s, 2H), 1.70 (s, 1H), 1.73-1.81 (m, 2H), 3.23-3.33 (m, 1H), 3.41-3.53 (m, 1H), 3.95-4.06 (m, 2H), 6.40-6.43 (m, 1H), 7.25-7.38 (m, 0.5H), 7.37-7.44 (m, 1.5H), 7.49-7.53 (m, 2H), 7.59-7.71 (m, 3.5H), 7.75 (q, 1H, J=1.8 Hz), 8.03-8.08 (m, 0.5H)
    • Example 84
  • 4-[5-[3-(4-hydroxybutyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00595
  • The above-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 83.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.50-1.62 (m, 4H), 1.68 (s, 1.5H), 1.73 (s, 1.5H), 3.62 (t, 2H, J=6.00 Hz), 3.94-3.98 (m, 2H), 6.44-6.46 (m, 1H), 7.42-7.79 (m, 8H), 8.10 (t, 1H, J=9.0 Hz).
    • Example 85
  • 4-[5-[3-(5-Aminopentyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile hydrochloride
  • Figure US20140179670A1-20140626-C00596
  • To a solution of tert-butyl 5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethyl)-2,3-dihydropyridin-1(6H)-yl]pentylcarbamate (prepared in Example 8) (12.0 mg) in ethanol (1.0 ml) was added 2N hydrochloric acid/ethanol (40 μl) and the resulting mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated under reduced pressure to afford 4-[5-[3-(5-aminopentyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile hydrochloride (10.4 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.26-1.34 (m, 2H), 1.44-1.68 (m, 4H), 1.88 (s, 1.5H), 1.91-(s, 1.5H), 2.86 (t, 2H, J=7.2 Hz), 3.80-3.87 (m, 2H), 6.58-(t, 1H, J=1.7 Hz), 7.68-7.91 (m, 9H)
    • Example 86
  • N-[5-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentyl]acetamide
  • Figure US20140179670A1-20140626-C00597
  • To a solution of 4-[5-[3-(5-aminopentyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile hydrochloride (prepared in Example 85) (6.4 mg) and triethylamine (10 μl) in dichloromethane (1.0 ml) was added acetyl chloride (0.7 mg) in ice-cooling and the resulting mixture was stirred for five minutes and stirred at room temperature for thirty minutes. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution (10 ml) and the resulting mixture was extracted with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-[5-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentyl]acetamide (3.0 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.18-1.24 (m, 2H), 1.42-1.52 (m, 4H), 1.66 (s, 1.5H), 1.71-(s, 1.5H), 1.84 (s, 3H), 3.10-3.18 (m, 2H), 3.80-3.87 (m, 2H), 5.51 (brs, 1H), 6.40 (d, 0.5H, J=7.0 Hz), 6.41 (d, 0.5H, J=7.0 Hz), 7.31-7.62 (m, 4H), 7.63-7.74 (m, 5H)
    • Example 87
  • N-[2-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]pentyl]menthanesulfonamide
  • Figure US20140179670A1-20140626-C00598
  • The above-mentioned compound was prepared by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 86.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.21-1.29 (m, 2H), 1.50-1.59 (m, 4H), 1.67 (s, 1.5H), 1.72-(s, 1.5H), 2.87 (s, 3H), 3.01-3.07 (m, 2H), 3.82-3.88 (m, 2H), 4.16 (brs, 1H), 6.42 (d, 0.5H, J=8.3 Hz), 6.43 (d, 0.5H, J=8.3 Hz), 7.36 (d, 0.5H, J=7.2 Hz), 7.45-7.54 (m, 3.5H), 7.62-7.75 (m, 5H)
    • Example 88
  • 4-(5-(2,4-Dioxo-3-(tetrahydro-2H-pyran-4-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00599
  • To a solution of 4-(5-(2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 53) (30 mg) in THF (2 ml) were added tetrahydro-2H-pyran-4-ol (0.014 ml), triphenylphosphine (37 mg) and diethyl azodicarboxylate (2.2 M toluene solution, 0.065 ml) and the resulting mixture was stirred at room temperature for fifteen minutes. The reaction solution was concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and reversed phase liquid chromatography (eluent: TFA water/acetonitrile) to afford-4-(5-(2,4-dioxo-3-(tetrahydro-2H-pyran-4-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (7 mg).
  • 1H-NMR (400 MHz, CDCl3) (δ PPM):
  • 1.46 (dd, 2H, J=2.2, 11.8 Hz), 2.61 (dd, 1H, J=4.7, 12.4 Hz), 2.67 (dd, 1H, J=4.7, 12.4 Hz), 3.42 (t, 2H, J=11.7 Hz), 4.03 (dd, 2H, J=4.4, 11.4 Hz), 4.96 (tt, 1H, J=4.0, 12.2 Hz), 6.53 (d, 1H, J=1.8 Hz), 7.51 (s, 1H), 7.57-7.60 (m, 2H), 7.62-7.66 (m, 2H), 7.68 (d, 1H, J=7.8 Hz), 7.74 (d, 1H, J=1.9 Hz), 7.76-7.78 (m, 3H)
    • Examples 89-92
  • The compounds indicated in the below-mentioned table (Examples 89-92) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 88.
    • Example 89
  • 4-(5-(3-(1-methylpiperidin-4-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 90
  • (S)-4-(5-2,4-dioxo-3-(5-oxopyrrolidin-3-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 91
  • 4-(5-(3-(1-(dimethylamino)propan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 92
  • 4-(5-(3-(oxetan-3-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00600
  • TABLE 49
    Measure-
    ment
    Ex. R1 cond. 1H-NMR (δ PPM)
    89
    Figure US20140179670A1-20140626-C00601
         		4 1.49 (d, 2H, J = 9.9 Hz), 2.03 (t, 2H, J = 1/1.5 Hz), 2.27 (s, 3H), 2.55-2.67 (m, 2H), 2.91 (d, 2H, J = 1/1.5 Hz), 4.69 (tt, 1H, J = 4.1, 12.2 Hz), 6.52 (d, 1H, J = 1.8 Hz), 7.50 (s, 1H), 7.59-7.67 (m, 5H), 7.73 (d, 1H, J = 1.8 Hz), 7.74- 7.77 (m, 3H)
    90
    Figure US20140179670A1-20140626-C00602
         		4 2.60 (dd, 1H, J = 10.6, 17.1 Hz), 2.73 (dd, 1H, J = 6.6, 17.1 Hz), 3.52 (dd, 1H, J = 5.6, 8.7 Hz), 3.67 (dd, 1H, J = 9.4, 10.8 Hz), 5.60 (brs, 1H), 5.75-5.85 (m, 1H), 6.57 (d, 1H, J = 1.8 Hz), 7.49 (s, 1H), 7.55-7.58 (m, 2H), 7.61-7.65 (m, 2H), 7.68 (t, 1H, J = 7.7 Hz), 7.75-7.79 (m, 4H)
    91
    Figure US20140179670A1-20140626-C00603
         		4 1.34 (d, 3H, J = 6.8 Hz), 2.08-2.20 (m, 1H), 2.15 (s, 6H), 3.16-3.24 (m, 1H), 5.05-5.15 (m, 1H), 6.52 (d, 1H, J = 1.8 Hz), 7.47 (s, 1H), 7.50-7.54 (m, 2H), 7.55- 7.62 (m, 3H), 7.64-7.69 (m, 3H), 7.3-7.77 (m, 1H)
    92
    Figure US20140179670A1-20140626-C00604
         		1 3.80 (dd, 2H, J = 1/1.4, 6.0 Hz), 4.04 (t, 2H, J = 10.2 Hz), 5.37-5.42 (m, 1H), 6.53 (s, 1H), 7.57-7.76 (m, 10H)
    • Example 93
  • 4-(4-Bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00605
  • To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (665 mg) in acetic acid (15 ml) was added at room temperature bromine (0.75 ml) dropwise and the resulting mixture was stirred at room temperature for fifteen minutes. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (30 ml) and the solids formed were filtered and then washed with hexane (50 ml) and dried under reduced pressure to afford 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (692.8 mg) as brown solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.73 (s, 1.5H), 1.78 (s, 1.5H), 3.33 (d, 3H, J=6.0 Hz), 7.48 (s, 1H), 7.54-7.58 (m, 3H), 7.71-7.77 (m, 4H), 7.81 (d, 1H, J=1.2 Hz)
    • Examples 94-100
  • The compounds indicated in the below-mentioned table (Examples 94-100) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 93.
    • Example 94
  • 4-(4-bromo-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 95
  • (R)-2-(5-(4-bromo-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propylacetate
    • Example 96
  • (R)-4-(4-bromo-5-(3-(1-hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 97
  • 4-(4-bromo-5-(3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 98
  • 2-(5-(4-bromo-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)ethylacetate
    • Example 99
  • 4-(4-bromo-5-(6-ethyl-1,3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 100
  • 4-(4-bromo-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00606
  • TABLE 50
    Measure-
    ment
    Ex. R1 R4 cond. 1H-NMR (δ PPM)
    94 iPr H 1 1.33 (d, 6H, J = 6.9 Hz), 5.01 (septet, 1H, J = 6.6 Hz), 7.58-
    7.74 (m, 9H), 7.76 (s, 1H)
    95
    Figure US20140179670A1-20140626-C00607
         		Me 1 1.37-1.46 (m, 3H), 1.68 (s, 1.5H), 1.73 (d, 1.5H, J = 3.3 Hz), 1.93 (s, 1H), 1.99-2.03 (m, 2H), 4.00-4.13 (m, 1H), 4.50-4.78 (m, 1H), 5.17 (brs, 1H), 7.34 (d, 0.25H, J = 7.5 Hz), 7.40 (d, 0.25H, J = 8.4 Hz), 7.48 (d, 0.5H, J = 13.2 Hz), 7.55-7.80 (m, 8H)
    96
    Figure US20140179670A1-20140626-C00608
         		H 1 1.25 (d, 3H, J = 7.2 Hz), 2.11 (brs, 1H), 3.65 (brd, 1H, J = 10.1 Hz), 3.84-3.94 (m, 1H), 4.96-5.04 (m, 1H), 5.03- 5.09 (m, 1H), 7.55-7.64 (m, 4H), 7.66-7.72 (m, 5H), 7.74 (s, 1H)
    97 Me H 1 3.26 (s, 3H), 7.53-7.57 (m, 3H), 7.61-7.71 (m, 6H), 7.74
    (s, 1H)
    98
    Figure US20140179670A1-20140626-C00609
         		Me 3 1.78 (s, 1.5H), 1.82 (s, 1.5H), 1.89 (s, 1.5H), 1.90 (s, 1.5H), 4.06-4.25 (m, 3H), 4.33-4.39 (m, 1H), 7.62-7.88 (m, 8H), 7.91 (s, 1H)
    99 Me Et 1 0.62 (t, 3H, J = 7.5 Hz), 1.85-2.15 (m, 2H), 3.39 (s, 1.5H),
    3.40 (s, 1.5H), 7.33 (d, 0.5H, J = 7.2 Hz), 7.44 (s, 0.5H),
    7.50 (d, 0.5H, J = 8.4 Hz), 7.57-7.68 (m, 3.5H), 7.71-7.78
    (m, 3H), 7.82 (d, 1H, J = 1.5 Hz)
    100 iPr Me 1 1.29 (t, 3H, J = 6.6 Hz), 1.34 (dd, 3H, J = 7.2, 2.7 Hz), 3.68
    (s, 1.5H), 1.72 (s, 1.5H), 4.94-5.05 (m, 1H), 7.36 (d,
    0.5H, J = 7.8 Hz), 7.42-7.46 (m, 1H), 7.50-7.55 (m,
    2.5H), 7.60-7.75 (m, 5H)
    • Example 101
  • 4-(4-Iodo-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00610
  • To a suspension of 4-(5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 42) (0.82 g) in acetonitrile (15 ml) were added iodine (0.26 g) and cerium ammonium nitrate (0.56 g) and the resulting mixture was stirred at 50° C. for one hour. The reaction mixture was cooled to room temperature, and thereto were added ethyl acetate (50 ml) and 5% aqueous sodium hydrogen sulfite solution (25 ml), and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-iodo-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (0.95 g) as white solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.36-1.38 (m, 6H), 1.61 (s, 1.5H), 1.66 (s, 1.5H), 4.97-5.08 (m, 1H), 7.33 (d, 0.5H, J=7.8 Hz), 7.43-7.55 (m, 3.5H), 7.59-7.73 (m, 4H), 7.78 (d, 1H, J=1.5H)
    • Example 102
  • 4-[5-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]-3-(methylsulfonyl)benzonitrile
  • Figure US20140179670A1-20140626-C00611
  • To a solution of 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]-3-methylthiobenzonitrile (prepared in Example 36) (6.5 mg) in dichloromethane (1.0 ml) were added under ice-cooling meta-chloro benzoyl peroxide (7.6 mg) and the resulting mixture was stirred at room temperature. After four hours, thereto was added under ice-cooling meta-chloro benzoyl peroxide (1.5 mg) and the resulting mixture was stirred at room temperature for three hours. To the resulting mixture was added chloroform (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (10 ml), and the organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]-3-(methylsulfonyl)benzonitrile.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.68 (s, 3H), 3.32 (s, 3H), 3.41 (s, 3H), 6.41 (d, 1H, J=1.8 Hz), 7.69 (d, 1H, J=8.1 Hz), 7.15-7.45 (m, 2H), 7.57 (t, 1H, J=7.2 Hz), 7.77 (d, 1H, J=1.8 Hz), 7.91 (d, 2H, J=1.5 Hz), 8.44 (s, 1H)
    • Example 103
  • 3-[5-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl]benzoic acid
  • Figure US20140179670A1-20140626-C00612
  • To a solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]phenylacetic acid methyl ester (prepared in Example 32) (239.6 mg) in tetrahydrofuran (2.0 ml) was added under ice-cooling sodium hydroxide (5M aqueous solution, 108 μl) and the resulting mixture was stirred at room temperature for twenty hours. The reaction mixture was washed with dietylether (15 ml), and the aqueous layer was acidified (pH=3) with potassium hydrogen sulfate and then extracted with ethyl acetate (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)benzoic acid (67.2 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.52 (s, 1.5H), 1.59 (s, 1.5H), 3.31 (d, 3H, J=2.4 Hz), 6.44 (d, 1H, J=1.8 Hz), 7.22-7.26 (m, 1H), 7.44 (s, 1H), 7.51-7.57 (m, 3H), 7.66-7.76 (m, 3H), 8.13 (s, 1H)
    • Example 104
  • 3-[5-[1-(4-Cyanophenyl)1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl]benzamide
  • Figure US20140179670A1-20140626-C00613
  • A solution of 3-[5-[1-(4-cyanophenyl)1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl]phenylacetic acid (prepared in Example 103), benzotriazol-1-yl-oxytripyrrolidine phosphonium hexafluorophosphate (30.8 mg), 1-hydroxy-7-azabenzotriazole (8.6 mg) and N,N-diethylisopropylamine (76 μl) in N,N-dimethy formamide (0.7 ml) was stirred at room temperature for thirty minutes. Thereto was added ammonium chloride (15.7 mg) and the resulting mixture was stirred at room temperature for twenty-two hours, and to the reaction mixture was added ethyl acetate (30 ml) and the resulting mixture was washed with 1M hydrochloric acid (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 3-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)benzamide (18.0 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.59 (s, 1.5H), 1.65 (s, 1.5H), 3.28 (s, 1.5H), 3.30 (s, 1.5H), 6.41 (dd, 1H, J=7.5, 1.8 Hz), 7.20-7.22 (m, 0.5H), 7.37-7.40 (m, 0.5H), 7.50-7.57 (m, 3H), 7.62-7.71 (m, 3H), 7.73-7.75 (m, 2H)
    • Examples 105-106
  • The compounds indicated in the below-mentioned table (Examples 105-106) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 104.
    • Example 105
  • 3-[5-[1-(4-cyanophenyl)1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl]-N-methylbenzamide
    • Example 106
  • 3-[5-[1-(4-cyanophenyl)1H-pyrazol-5-yl]-3,6-dimethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl]-N,N-dimethylbenzamide
  • Figure US20140179670A1-20140626-C00614
  • TABLE 51
    Measure-
    ment
    Ex. Ar1 cond. 1H-NMR (δ PPM)
    105
    Figure US20140179670A1-20140626-C00615
         		1 1.58 (s, 1.5H), 1.66 (s, 1.5H), 2.95 (dd, 3H, J = 4.8, 1.5 Hz), 3.30 (d, 3H, J = 8.1 Hz), 6.21 (brs, 1H), 6.40 (dd, 1H, J = 9.0, 1.8 Hz), 7.14-7.18 (m, 1H), 7.31-7.34 (m, 1H), 7.50-7.57 (m, 3H), 7.65-7.75 (m, 4H)
    106
    Figure US20140179670A1-20140626-C00616
         		1 1.59 (s, 1.5H), 1.66 (s, 1.5H), 2.94 (s. 1.5H), 2.95 (s, 1.5H), 3.05 (s, 3H), 3.30 (d, 3H, J = 6.0 Hz), 6.39 (dd, 1H, J = 2.4, 1.8 Hz), 7.06- 7.08 (m, 0.5H), 7.14-7.15 (m, 0.5H), 7.23-7.28 (m, 1H), 7.48-7.53 (m, 4H), 7.65-7.68 (m, 2H), 7.74 (t, 1H, J = 1.8 Hz)
    • Example 107
  • 4-(5-(1-(Biphenyl-3-yl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00617
  • A solution of 4-[5-[1-(3-bromophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-H-pyrazol-1-yl]benzonitrile (prepared in Example 34) (2.2 mg), phenylboronic acid (2.3 mg), tetrakis(triphenylphosphine)palladium (2.4 mg) and sodium carbonate (2.2 mg) in N,N-dimethy formamide/water=1/1 (1.0 ml) was stirred at 100° C. for one hour. To the reaction mixture was added ethyl acetate (30 ml) and the resulting mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford 4-(5-(1-(biphenyl-3-yl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (2.3 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.63 (d, 3H, J=1.8 Hz), 3.32 (s, 3H), 6.42 (dd, 1H, J=4.2, 1.8 Hz), 6.97-7.00 (m, 0.5H), 7.15-7.18 (m, 0.5H), 7.37-7.55 (m, 9H), 7.63-7.69 (m, 3H), 7.75 (t, 1H, J=1.5 Hz)
    • Example 108
  • 4-[5-[3,6-Dimethyl-2,4-dioxo-1-(3-ethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile
  • Figure US20140179670A1-20140626-C00618
  • To a solution of 4-[5-[1-(3-bromophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 34) (15.5 mg) and bis(tri-t-butylphosphine)palladium (1.0 mg) in tetrahydrofuran (1.0 ml) was added zinc diethyl (1.0 M normal hexane solution, 0.06 ml) and the resulting mixture was stirred at 60° C. for thirty minutes. To the reaction mixture was added ethyl acetate (30 ml) and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-ethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (3.6 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.16-1.22 (m, 3H), 1.58 (s, 3H), 2.61-2.68 (m, 2H), 3.30 (s, 3H), 6.41 (d, 1H, J=1.8 Hz), 6.81 (d, 1H, J=6.6 Hz), 6.99 (d, 1H, J=9.0 Hz), 7.25 (d, 1H, J=7.8 Hz), 7.23-7.39 (m, 1H), 7.52 (dd, 2H, J=8.4, 3.9 Hz), 7.67 (dd, 2H, J=8.4, 3.3 Hz), 7.74 (d, 1H, J=1.8 Hz)
    • Example 109
  • (R)-4-(5-(3-(1-Hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00619
  • To a solution of (R)-2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (prepared in example 47) (31.9 mg) in ethanol (1.0 ml) was added under ice-cooling 1M aqueous sodium hydroxide solution (65.2 μl) and the resulting mixture was stirred for one hour under ice-cooling. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with 1M hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(1-hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (24.6 mg) as brown solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.25-1.39 (m, 3H), 1.65 (s, 1.5H), 1.70 (s, 1.5H), 2.57-(brs, 1H), 3.64-3.73 (m, 1H), 3.88-4.01 (m, 1H), 5.08 (brs, 1H), 6.46 (d, 1H, J=7.2 Hz), 7.35-7.78 (m, 9H)
    • Example 110
  • (R)-4-(5-(3-(1-Hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-methyl-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00620
  • The intended compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 109.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.21-1.40 (m, 3H), 1.56 (d, 1.5H, J=1.5 Hz), 1.61 (d, 1.5H, J=1.5 Hz), 2.02-2.04 (m, 3H), 3.75 (brs, 1H), 3.98 (brs, 1H), 5.13 (brs, 1H), 7.31-7.55 (m, 4H), 7.66-7.78 (m, 5H)
    • Example 111
  • (R)-4-(5-(3-(1-Hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00621
  • The intended compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 102.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.33 (d, 3H, J=7.0 Hz), 2.30 (brs, 1H), 3.73 (dd, 1H, J=11.8, 3.8 Hz), 3.98 (t, 1H, J=9.0 Hz), 5.07-5.14 (m, 1H), 6.51 (d, 1H, J=1.7 Hz), 7.50 (s, 1H), 7.55-7.68 (m, 5H), 7.71-7.75 (m, 4H)
    • Examples 112-113
  • Figure US20140179670A1-20140626-C00622
    • Example 112
  • 4-(5-(3-(Azetidin-3-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • The intended compound was obtained by using the starting materials prepared in Example 45 according to the similar reaction and treatment method to those described in Example 72.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.85 (d, 3H, J=5.7 Hz), 4.06-4.47 (m, 4H), 5.33-5.53 (m, 1H), 6.58-6.64 (m, 1H), 7.48-7.88 (m, 9H)
    • Example 113
  • 4-(5-(3-(1-Acetylazetidin-3-yl)-6-methyl-2,4-dioxo)-1H-pyrazol-1-yl)benzonitrile-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl
  • The intended compound was obtained by using 4-(5-(3-(azetidin-3-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 112) according to the similar reaction and treatment method to those described in Example 86.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.66-1.70 (m, 3H), 1.80-1.84 (m, 3H), 4.17-4.53 (m, 4H), 5.31-5.42 (m, 1H), 6.45 (dd, 1H, J=5.7, 1.5 Hz), 7.32 (d, 1H, J=9.3 Hz), 7.39 (s, 0.5H), 7.47 (d, 0.5H, J=8.1 Hz), 7.56 (dd, 2H, J=9.0, 2.4 Hz), 7.65-7.80 (m, 5H)
    • Example 114
  • 4-(5-(6-Methyl-3-(1-methylazetidin-3-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00623
  • The intended compound was obtained by using 4-(5-(3-(azetidin-3-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 112) and formaldehyde according to the similar reaction and treatment method to those described in Example 69.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.61 (s, 1.5H), 1.65 (s, 1.5H), 2.25 (d, 3H, J=1.5 Hz), 2.66-2.78 (m, 1H), 2.95 (t, 1H, J=6.9 Hz), 3.82-3.88 (m, 2H), 4.37-4.49 (m, 1H), 6.40 (dd, 1H, J=6.9, 1.5 Hz), 7.27 (d, 1H, J=8.4 Hz), 7.35 (s, 0.5H), 7.40 (d, 0.5H, J=8.4 Hz), 7.49-7.54 (m, 2H), 7.58-7.61 (m, 1H), 7.68-7.74 (m, 4H)
    • Examples 115-117
  • Figure US20140179670A1-20140626-C00624
    • Example 115
  • 4-(5-(6-(bromomethyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 116
  • 4-(5-(6-(dibromomethyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • To a solution of 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 1) (30.0 mg) in tetrahydrofuran (1.0 ml) was added at 0° C. lithium hexamethyldisilazide (0.1 ml: IM tetrahydrofuran solution) followed by an addition of N-bromosuccinimide (14.4 mg), and the resulting mixture was stirred at 0° C. for a half hour. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 ml) and the mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-(6,6-dibromomethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (5.4 mg) and 4-[5-(6-bromomethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (6.9 mg). 4-(5-(6-(Bromomethyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile:
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 3.29 (s, 1.5H), 3.30 (s, 1.5H), 3.65 (d, 0.5H, J=11.0 Hz), 3.68 (d, 0.5H, J=11.0 Hz), 3.99 (d, 0.5H, J=11.0 Hz), 4.01 (d, 0.5H, J=11.0 Hz), 6.60 (d, 0.5H, J=1.8 Hz), 6.10 (d, 0.5H, J=1.8 Hz), 7.58-7.74 (m, 7H), 7.80-7.84 (m, 2H)
  • 4-(5-(6-(Dibromomethyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 3.27 (s, 1.5H), 3.28 (s, 1.5H), 3.44 (s, 0.5H), 3.47 (s, 0.5H), 6.68 (d, 1H, J=1.5 Hz), 7.61 (d, 2H, J=6.8 Hz), 7.68-7.77 (m, 4H), 7.82 (s, 1H), 7.84-7.87 (m, 2H)
    • Example 117
  • 4-(5-(6-((Dimethylamino)methyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • To a solution of 4-[5-(6-bromomethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 115) (20.0 mg) in acetonitrile (1.0 ml) was added at room temperature dimethyl amine (40 μl: 1M tetrahydrofuran solution) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-(6-(dimethylamino)methyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (5.1 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 11.55 (s, 3H), 1.58 (s, 3H), 2.52-2.61 (m, 2H), 3.34 (s, 1.5H), 3.36 (s, 1.5H), 6.38 (d, 0.5H, J=1.8 Hz), 6.42 (d, 0.5H, J=1.8 Hz), 7.50-7.58 (m, 4H), 7.60-7.69 (m, 4H), 7.75 (d, 0.5H, J=1.8 Hz), 7.76 (d, 0.5H, J=1.8 Hz)
    • Example 118
  • 4-(5-(6-(Hydroxymethyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00625
  • To a solution of 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 1) (50.0 mg) in dioxane (1.0 ml) were added acetic acid (0.5 ml) and selenium dioxide (74.0 mg) and the resulting mixture was stirred with heating under reflux for six hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-(6-hydroxymethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (3.7 mg).
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 3.23 (s, 1.5H), 3.25 (s, 1.5H), 3.93 (dd, 1H, J=11.8, 5.6 Hz), 4.15 (d, 1H, J=11.8 Hz), 6.46 (t, 1H, J=2.1 Hz), 7.46-7.74 (m, 9H)
    • Example 119
  • (R)-4-(5-(3-(1-Methoxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00626
  • To a solution of (R)-4-(5-(3-(1-hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 111) (95.1 mg) in dichloromethane (1.0 ml) were added under ice-cooling trifluoromethanesulfonic anhydride (50.2 μl) and N,N-diisopropylethylamine (70.2 μl) and the resulting mixture was stirred under ice-cooling for one hour. To the reaction mixture was added methanol (5 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(1-methoxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (51.0 mg) as pale yellow solid.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.31 (d, 3H, J=7.2 Hz), 3.25 (s, 3H), 3.33 (dd, 1H, J=7.2, 2.5 Hz), 3.99 (t, 1H, J=9.9 Hz), 5.14-5.25 (m, 1H), 6.51 (s, 1H), 7.49 (s, 1H), 7.56-7.66 (m, 5H), 7.70-7.74 (m, 4H)
    • Example 120
  • (R)-2-(5-(1-(4-Cyanophenyl)-1H-pyrazol-5-yl)-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propylmethane sulfonate
  • Figure US20140179670A1-20140626-C00627
  • To a solution of (R)-4-(5-(3-(1-hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 111) (17.3 mg) in dichloromethane (1.0 ml) was added under ice-cooling methanesulfonyl chloride (5.6 μl) and triethylamine (10.0 μl) and the resulting mixture was stirred under ice-cooling for fifteen minutes. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (1 ml) followed by an addition of ethyl acetate (50 ml), and the resulting mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-2-(5-(1-(4-cyanophenyl)-1H-pyrazole-5-yl)-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propylmethanesulfonate (2.6 mg) as brown solid.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.39 (d, 3H, J=7.2H), 2.94 (s, 3H), 4.04-4.11 (m, 2H), 5.28-5.32 (m, 1H), 6.51 (d, 1H, J=1.8 Hz), 7.33 (s, 1H), 7.51-7.73 (m, 9H)
    • Example 121
  • 2-(5-(1-(4-Cyanophenyl)-1H-pyrazol-5-yl)-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propionic acid
  • Figure US20140179670A1-20140626-C00628
  • The intended compound was prepared by using the compound prepared in Example 26 according to the similar reaction and treatment method to those described in Example 85.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.45 (d, 3H, J=7.0 Hz), 5.38 (q, 1H, J=7.0 Hz), 6.66 (d, 1H, J=1.8 Hz), 7.73-7.83 (m, 8H), 7.89 (s, 1H), 8.08 (s, 1H)
    • Example 122
  • (S)-5-(1-(4-Bromophenyl)-1H-pyrazol-5-yl)-3-(1-hydroxypropan-2-yl)-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione
  • Figure US20140179670A1-20140626-C00629
  • To a solution of (S)-ethyl 2-(5-(1-(4-bromophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propanoate (prepared in Example 46) (51.6 mg) in dichloromethane (0.9 ml) was added a solution of diisobutylaluminium hydride in hexane (1.0 M, 0.21 ml) at −78° C. and the resulting mixture was stirred at −78° C. for seven hours. To the reaction mixture were added 2M aqueous potassium sodium tartrate solution (1 ml) and diethylther (20 ml) and the resulting mixture was stirred at room temperature for thirty minutes. To the reaction mixture was then added ethyl acetate (50 ml) and the resulting mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (1.0 ml) and thereto was added at 0° C. sodium borohydride (4.9 mg) and the resulting mixture was stirred at room temperature for two hours. To the reaction mixture was added 1M hydrochloric acid and the resulting mixture was stirred at room temperature for thirty minutes. To the reaction mixture was then added ethyl acetate (50 ml) and the mixture was washed with water (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (S)-5-(1-(4-bromophenyl)-1H-pyrazol-5-yl)-3-(1-hydroxypropan-2-yl)-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (15.0 mg) as colorless liquid.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.27-1.35 (m, 3H), 1.54 (d, 3H, J=5.1 Hz), 3.65-3.76 (m, 1H), 3.87-3.97 (m, 1H), 5.08 (brs, 1H), 6.40 (dt, 1H, J=4.5, 1.8 Hz), 7.23 (dt, 1.5H, J=8.7, 1.5 Hz), 7.30 (d, 0.5H, J=5.4 Hz), 7.37-7.42 (m, 1H), 7.47-7.63 (m, 5H), 7.68-7.71 (m, 1H)
    • Example 123
  • (S)-4-(5-(3-(1-Hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00630
  • To a solution of (S)-5-(1-(4-bromophenyl)-1H-pyrazol-5-yl)-3-(1-hydroxypropan-2-yl)-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Example 122) (5.0 mg) in N,N-dimethy formamide (1.0 ml) were added zinc cyanide (10.3 mg), zinc dust (1.2 mg) and tetrakis(triphenylphosphine)palladium (5.3 mg) and the resulting mixture was stirred at 120° C. for four hours. The reaction mixture was filtered and thereto was added ethyl acetate (50 ml) and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (S)-4-(5-(3-(1-hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (1.9 mg) as white solid.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.30-1.37 (m, 3H), 1.66 (d, 1.5H, J=1.8 Hz), 1.70 (d, 1.5H, J=1.8 Hz), 3.71-3.81 (m, 1H), 3.92-4.00 (m, 1H), 5.10 (brs, 1H), 6.43-6.45 (m, 1H), 7.2,6-7.30 (m, 1H), 7.49-7.59 (m, 3H), 7.64-7.80 (m, 5H)
    • Example 124
  • 6-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)nicotinonitrile
  • Figure US20140179670A1-20140626-C00631
  • The intended compound was obtained by using the compound prepared in Example 24 according to the similar reaction and treatment method to those described in Example 123.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.38 (d, 3H, J=7.0 Hz), 1.45 (d, 3H, J=7.0 Hz), 1.79 (s, 1.5H), 1.80 (s, 1.5H), 5.04-5.13 (m, 1H), 6.42 (d, 0.5H, J=1.7 Hz), 6.45 (d, 0.5H, J=1.7 Hz), 7.50 (t, 1H, J=7.7 Hz), 7.55-7.58 (m, 2H), 7.68 (t, 1H, J=7.8 Hz), 7.75 (t, 1H, J=8.1 Hz), 7.80 (t, 1H, J=1.5 Hz), 8.02 (d, 0.5H, J=2.2 Hz), 8.04 (d, 0.5H, J=2.2 Hz), 8.01 (d, 0.5H, J=2.2 Hz), 8.03 (d, 0.5H, J=2.2 Hz), 8.14 (d, 0.5H, J=0.8 Hz), 8.17 (d, 0.5H, J=0.8 Hz), 8.51 (d, 0.5H, J=2.2 Hz), 8.55 (d, 0.5H, J=2.2 Hz)
    • Example 125
  • 4-(4-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)nicotinonitrile
  • Figure US20140179670A1-20140626-C00632
  • The intended compound was obtained by using the compound prepared in Example 67 according to the similar reaction and treatment method to those described in Example 123.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.45 (t, 6H, J=6.7 Hz), 1.71 (s, 3H), 5.08-5.17 (m, 1H), 7.49-7.61 (m, 2H), 7.72 (t, 1H, J=7.5 Hz), 7.80 (d, 1H, J=7.7 Hz), 8.10 (dd, 1H, J=8.2, 1.9 Hz), 8.24 (d, 1H, J=5.0 Hz), 8.57 (d, 1H, J=8.4 Hz), 8.74-8.78 (m, 1H)
    • Example 126
  • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-methyl-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00633
  • The intended compound was obtained by using the compound prepared in Example 93 according to the similar reaction and treatment method to those described in Example 108.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.49 (s, 1.5H), 1.55 (s, 1.5H), 1.98 (s, 3H), 3.31 (d, 3H, J=7.2 Hz), 7.22-7.42 (m, 1.5H), 7.46-7.50 (m, 2.5H), 7.58-7.73 (m, 5H)
    • Examples 127-131
  • The compounds indicated in the below-mentioned table (Examples 127-131) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 108.
    • Example 127
  • acetic acid (R)-2-(5-(1-(4-cyanophenyl)-4-methyl-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propylester
    • Example 128
  • 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-propyl-1H-pyrazol-1-yl)benzonitrile
    • Example 129
  • (R)-4-(5-(3-(1-hydroxypropan-2-yl)-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(propa-1-en-2-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 130
  • 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(propa-1-en-2-yl)-1H-pyrazol-1-yl)benzonitrile
    • Example 131
  • 4-(5-(6-ethyl-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-methyl-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00634
  • TABLE 52
    Measure-
    ment 1H-NMR (δ PPM)
    Ex. R1 R4 R″ cond. (or LC-MS: [M + H]+/Rt)
    127
    Figure US20140179670A1-20140626-C00635
         		Me Me 4 1.41-1.55 (m, 6H), 1.96-2.04 (m, 6H), 4.03-4.27 (m, 1H), 4.60-4.83 (m, 1H), 5.19 (brs, 1H), 7.21-7.47 (m, 1H), 7.53- 7.76 (m, 8H)
    128 Me Me nPr 1 0.94 (dt, 3H, J = 7.2, 3.0 Hz), 1.48 (s, 1.5H),
    1.54 (s, 1.5H), 1.56-1.66 (m, 2H), 2.28-
    2.35 (m, 2H), 3.37 (s, 1.5H), 3.39 (s,
    1.5H), 7.21 (d, 0.5H, J = 9.6 Hz), 7.32 (s,
    0.5H), 7.44 (d, 0.5H, J = 8.4 Hz), 7.49-7.54
    (m, 2.5H), 7.61-7.76 (m, 5H)
    129
    Figure US20140179670A1-20140626-C00636
         		H
    Figure US20140179670A1-20140626-C00637
         		1 1.33 (d, 3H, J = 7.2 Hz), 1.99 (s, 3H), 2.22- 2.28 (m, 1H), 3.72 (dd, 1H, J = 12.1, 1.5 Hz), 3.92-4.00 (m, 1H), 5.00 (s, 1H), 5.05 (s, 1H), 5.08-5.14 (m, 1H), 7.31 (s, 1H), 7.41-7.46 (m, 2H), 7.54 (d, 2H, J = 8.4 Hz), 7.59 (d, 1H, J = 8.3 Hz), 7.64- 7.68 (m, 3H), 7.72 (s, 1H)
    130 Me Me
    Figure US20140179670A1-20140626-C00638
         		9 492.1 (M + H)/1.124 (min)
    131 Me Et Me 1 0.53 (dt, 3H, J = 7.2, 3.6 Hz), 1.76-1.97 (m,
    2H), 2.02-2.03 (m, 4H), 3.41 (s, 1.5H),
    3.42 (s, 1.5H), 7.28 (d, 0.5H, J = 9.0 Hz),
    7.37 (s, 0.5H), 7.47 (d, 0.5H, J = 7.5 Hz),
    7.54-7.60 (m, 2.5H), 7.63-7.76 (m, 4H)
    • Example 132
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid
  • Figure US20140179670A1-20140626-C00639
  • To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (139.8 mg) in 1,4-dioxane (2.0 ml) were added tetrakis(triphenylphosphine)palladium (30.7 mg),N,N-diisopropylethylamine (46.8 μl) and water (0.5 ml) and the resulting mixture was stirred at 100° C. under carbon monoxide atmosphere for four hours. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with 1M hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (24.5 mg) as brown solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.66 (s, 1.5H), 1.69 (s, 1.5H), 3.33 (d, 3H, J=7.5 Hz), 7.30 (d. 0.5H, J=8.1 Hz), 7.42-7.49 (m, 1.5H), 7.56-7.71 (m, 3H), 7.75-7.79 (m, 2H), 8.08 (dd, 1H, J=8.4, 1.2 Hz), 8.27 (d, 1H, J=1.2 Hz)
    • Example 133
  • 1-(4-Cyanophenyl)-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid
  • Figure US20140179670A1-20140626-C00640
  • The intended compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 132.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.33-1.41 (m, 6H), 1.63 (s, 1.5H), 1.66 (s, 1.5H), 5.00-5.09 (m, 1H), 7.37 (d, 0.5H, J=9.1 Hz), 7.46 (d, 1H, J=6.6 Hz), 7.55 (s, 0.5H), 7.60-7.68 (m, 3H), 7.73-7.79 (m, 3H), 8.25 (d, 1H, J=2.1 Hz)
    • Example 134
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid methyl ester
  • Figure US20140179670A1-20140626-C00641
  • To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (50.4 mg) in 1,4-dioxane (1.0 ml) were added bis(tri-tert-butylphosphine)palladium (4.9 mg),N,N-diisopropylethylamine (32.0 L) and methanol (1.0 mL), and the resulting mixture was stirred at 10° C. under carbon monoxide atmosphere for four hours. To the reaction mixture was added ethyl acetate (100 ml) and the resulting mixture was washed with water (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford methyl-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate (9.4 mg) as white solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.63 (s, 1.5H), 1.70 (s, 1.5H), 3.31 (d, 3H, J=9.0 Hz), 3.83 (d, 3H, J=3.0 Hz), 7.30 (d, 0.5H, J=8.1 Hz), 7.43 (s, 0.5H), 7.52-7.78 (m, 7H), 8.18 (d, 1H, J=1.2 Hz)
    • Example 135
  • 4-(4-Acetyl-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00642
  • To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (54.6 mg) in 1,4-dioxane (1.0 ml) were added tetrakis(triphenylphosphine)palladium (23.8 mg) and tributyl(1-ethoxyvinyl)tin (103.4 μl) and the resulting mixture was stirred for one hour with heating in microwave instrument (120° C.). To the reaction mixture were then added 1M hydrochloric acid (1 mL) and ethyl acetate (2 ml) and the resulting mixture was stirred at room temperature for one hour. To the reaction mixture was ethyl acetate (50 ml) and the mixture was washed with 10% aqueous potassium carbonate solution (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-acetyl-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (19.0 mg) as white solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.61 (s, 1.5H), 1.68 (s, 1.5H), 2.50 (s, 3H), 3.26 (s, 1.5H), 3.30 (s, 1.5H), 7.30 (d, 0.5H, J=8.4 Hz), 7.44 (s, 0.5H), 7.60-7.63 (m, 4H), 7.73-7.77 (m, 3H), 8.19 (d, 1H, J=0.9 Hz)
    • Example 136
  • 4-(4-Acetyl-5-(2,4-dioxo-3-isopropyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00643
  • The intended compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 135.
  • 1H-NMR 300 MHz, CDCl3) (δ PPM):
  • 1.24 (d, 6H, J=3.3 Hz), 2.48 (s, 3H), 4.93 (quin, 1H, J=6.9 Hz), 7.57-7.77 (m, 8H), 7.94 (s, 1H), 8.11 (s, 1H)
    • Example 137
  • 4-(4-(2-Hydroxypropan-2-yl)-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00644
  • To a solution of 4-(4-acetyl-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 136) (28.2 mg) in tetrahydrofuran (1.0 ml) was added under ice-cooling methyl magnesium chloride (3.0 M tetrahydrofuran solution, 27.8 μl) dropwise and the resulting mixture was stirred under ice-cooling for one hour. To the resulting mixture was water (1 mL) followed by an addition of ethyl acetate (50 ml), and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-(2-hydroxypropan-2-yl)-5-(3-isopropyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (4.3 mg) as white solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.29 (s, 3H), 1.39 (dd, 3H, J=12.0, 6.0 Hz), 1.55 (s, 6H), 2.98 (s, 1H), 4.93 (quin, 0.33H, J=6.9 Hz), 5.11 (quin, 0.67H, J=6.6 Hz), 7.38-7.72 (m, 8H), 7.79 (s, 0.33H), 7.92 (s, 0.33H), 8.11 (s, 0.33H)
    • Example 138
  • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(hydroxymethyl)-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00645
  • To a solution of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (prepared in Example 132) (100 mg) and N-methylmorpholine (66 μL) in tetrahydrofuran (2 ml) was added at 0° C. isobutyl chloroformate (79 μl). After thirty minutes, to the reaction mixture was added sodium borohydride (26.4 mg) and the resulting mixture was stirred for three and a half hours. Thereto was added sodium borohydride (55.6 mg) and the mixture was stirred for another thirty minutes and thereto were added water and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over sodium sulfate, and then concentrated on evaporator instrument. The residue was purified by silica gel column chromatography to afford the intended 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(hydroxymethyl)-1H-pyrazol-1-yl)benzonitrile.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.36 (s, 1.5H), 1.39 (s, 1.5H), 3.43 (s, 1.5H), 3.44 (s, 1.5H), 4.46 (s, 2H), 7.07 (d, 0.5H, J=8.1H), 7.13 (s, 0.5H), 7.45 (d, 0.5H, J=8.4 Hz), 7.52 (dd, 2H, J=8.7, 1.5 Hz), 7.57 7.68 (m, 1H), 7.72-7.77 (m, 3.5H), 7.86 (d, 1H, J=2.7 Hz)
    • Examples 139-141
  • Figure US20140179670A1-20140626-C00646
    • Example 139
  • 4-[5-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-4-nitro-1H-pyrazol-1-yl]benzonitrile
  • The intended compound was obtained according to the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 192.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.62 (s, 1.5H), 1.68 (s, 1.5H), 3.27 (s, 1.5H), 3.29 (s, 1.5H), 7.25 (d, 0.5H, J=6.6 Hz), 7.37 (s, 0.5H), 7.47 (d, 0.5H, J=7.8 Hz), 7.53-7.69 (m, 3.5H), 7.73-7.78 (m, 3H), 8.39 (s, 1H)
    • Example 140
  • 4-(4-amino-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile
  • The intended compound was obtained according to the corresponding starting materials according to the similar reaction and treatment method to those described in Reference Example 193.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.49 (s, 1.5H), 1.51 (s, 1.5H), 3.40 (s, 1.5H), 3.41 (s, 1.5H), 7.17 (d, 0.5H, J=8.1 Hz), 7.23 (d, 0.5H, J=8.7 Hz), 7.43-7.52 (m, 4H), 7.61-7.91 (m, 4H)
    • Example 141
  • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(dimethylamino)-1H-pyrazol-1-yl)benzonitrile
  • The intended compound was obtained according to the corresponding starting materials according to the similar reaction and treatment method to those described in Example 69.
  • 1H-NMR (CDCl3: 300 MHz) (δ PPM):
  • 1.56 (s, 1.5H), 1.62 (s, 1.5H), 2.63 (s, 3H), 2.64 (s, 3H), 3.30 (s, 1.5H), 3.32 (s, 1.5H), 7.23 (s, 0.5H), 7.33 (s, 0.5H), 7.39 (d, 1H, J=7.5 Hz), 7.45-7.49 (m, 2.5H), 7.53 (d, 1H, J=1.2 Hz), 7.60-7.66 (m, 2.5H), 7.71 (d, 1H, J=7.5 Hz)
    • Example 142
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-methyl-1H-pyrazole-4-carboxamide
  • Figure US20140179670A1-20140626-C00647
  • The intended compound was obtained according to the corresponding starting materials according to the similar reaction and treatment method to those described in Example 75.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.55 (s, 1.5H), 1.64 (s, 1.5H), 2.86 (s, 0.75H), 2.88 (s, 0.75H), 2.90 (s, 0.75H), 2.93 (s, 0.75H), 3.32 (s, 1.5H), 3.36 (s, 1.5H), 6.24-6.30 (m, 1H), 7.18 (d, 0.5H, J=8.4 Hz), 7.32 (s, 0.5H), 7.53-7.69 (m, 4H), 7.72-7.77 (m, 3H), 7.98-(d, 1H, J=6.9 Hz)
    • Examples 143-145
  • The compounds indicated in the below-mentioned table (Examples 143-145) were obtained according to the corresponding starting materials according to the similar reaction and treatment method to those described in Example 75.
    • Example 143
  • 1-(4-cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide
    • Example 144
  • 1-(4-cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-methyl-1H-pyrazole-4-carboxamide
    • Example 145
  • 1-(4-cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide
  • Figure US20140179670A1-20140626-C00648
  • TABLE 53
    Measurement
    Ex. R1 R4 R″ cond 1H-NMR (δ PPM)
    143 iPr Me NH2 4 1.38 (d, 1.5H, J = 6.9 Hz), 1.42 (d, 1.5H, J = 6.9 Hz),
    1.43 (d, 1.5H, J = 7.0 Hz), 1.45 (d, 1.5H, J = 7.0 Hz),
    1.56 (s, 1.5H), 1.64 (s, 1.5H), 5.00-5.15 (m, 1H),
    5.50 (brs, 1H), 6.02 (brs, 1H), 7.20-7.25 (m,
    0.5H), 7.32 (s, 0.5H), 7.53-7.67 (m, 4H),
    7.78-7.81 (m, 3H), 8.06 (s, 0.5H), 8.07 (s, 0.5H)
    144 iPr Me NHMe 1 1.32-1.50 (m, 6H), 1.52 (s, 1H), 1.61 (s, 1H),
    1.65 (d, 1H, J = 9.9 Hz), 2.92 (s, 1.5H), 2.93 (s,
    1.5H), 5.03-5.14 (m, 1H), 7.53-7.79 (m, 9H),
    7.99 (d, 1H, J = 5.4 Hz)
    145 Me Me NMe2 1 1.54 (s, 1.5H), 1.59 (s, 1.5H), 2.87 (s, 1H),
    2.95 (s. 1H), 3.00 (brs, 2H), 3.13 (brs, 2H), 3.29 (s,
    1.5H), 3.30 (s, 1.5H), 7.14 (d, 1H, J = 1.8 Hz),
    7.26 (s, 0.5H), 7.45-7.63 (m, 4H), 7.67-7.73 (m,
    2.5H), 7.80 (d, 1H, J = 1.8 Hz)
    • Example 146
  • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-isopropyl-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00649
  • The intended 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-isopropyl-1H-pyrazol-1-yl)benzonitrile was obtained by using 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(propa-1-en-2-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 130) according to the similar reaction and treatment method to those described in Example 72.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.15-1.21 (m, 6H), 1.41 (s, 1.5H), 1.46 (s, 1.5H), 1.71 (s, 0.5H), 1.76 (s, 0.5H), 2.61 (q, 1H, J=7.8 Hz), 3.81-3.85 (m, 2H), 4.19-4.23 (m, 2H), 7.13-7.17 (m, 1H), 7.45-7.55 (m, 3H), 7.59-7.72 (m, 5H)
    • Example 147
  • 4-(5-(3-(2-Hydroxyethyl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-isopropyl-1H-pyrazol-1-yl)benzonitrile
  • Figure US20140179670A1-20140626-C00650
  • To a solution of 2-(5-(4-bromo-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)ethyl acetate (prepared in Example 98) (220.3 mg) in dimethoxyethane (4.0 ml) were added isopropenyl boronic acid pinacol ester (69.0 μl), tetrakis(triphenylphosphine)palladium (85.2 mg), sodium carbonate (194.3 mg) and water (0.4 ml) and the resulting mixture was stirred at 100° C. for seven hours. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with water (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a solution of the residue in methanol (4 ml) was added palladium carbon (28.7 mg) and the resulting mixture was stirred at room temperature under hydrogen atmosphere for six hours. The reaction mixture was filtered through Celite (trade mark) and then concentrated under reduced pressure. To a solution of the residue in methanol (5 ml) was added under ice-cooling 1M aqueous potassium carbonate solution (392 μl) and the resulting mixture was stirred under ice-cooling for one hour. To the reaction mixture was added 1M hydrochloric acid (329 μl) and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate) to afford 4-(5-(3-(2-hydroxyethyl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-isopropyl-1H-pyrazol-1-yl)benzonitrile (62.6 mg) as white solid.
  • 1H-NMR (300 MHz, CDCl3) (δ PPM):
  • 1.15-1.21 (m, 6H), 1.41 (s, 1.5H), 1.46 (s, 1.5H), 1.71 (s, 0.5H), 1.76 (s, 0.5H), 2.61 (q, 1H, J=7.8 Hz), 3.81-3.85 (m, 2H), 4.19-4.23 (m, 2H), 7.13-7.17 (m, 1H), 7.45-7.55 (m, 3H), 7.59-7.72 (m, 5H)
    • Examples 148-179
  • The compounds indicated in the below-mentioned table (Examples 148-179) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 142.
  • Figure US20140179670A1-20140626-C00651
  • TABLE 54
    Measurement (LC-MS: Rt/
    Ex. R R1 m.p. cond. [M + H]+)
    148 NH2 Me 263 9 0.86 495
    149 NH2 Et 9 0.85 509
    150 NHEt Me 9 0.89 523
    151 NHEt i-Pr 258 9 0.99 551
    152 NHEt Et 242 9 0.93 537
    153 NMe2 i-Pr 9 0.96 551
    154 NMe2 Et 193 9 0.90 537
    155
    Figure US20140179670A1-20140626-C00652
         		Me 9 0.91 535
    156
    Figure US20140179670A1-20140626-C00653
         		Et 9 0.83 565
    157
    Figure US20140179670A1-20140626-C00654
         		Me 235 9 0.79 551
    158
    Figure US20140179670A1-20140626-C00655
         		Et 167 9 0.94 579
    159
    Figure US20140179670A1-20140626-C00656
         		Me 244 9 0.91 565
    160
    Figure US20140179670A1-20140626-C00657
         		Me 9 0.84 565
    161
    Figure US20140179670A1-20140626-C00658
         		Et 9 0.99 585
    162
    Figure US20140179670A1-20140626-C00659
         		Me 227 9 0.91 549
    163
    Figure US20140179670A1-20140626-C00660
         		Et 9 0.99 599
  • TABLE 55
    164
    Figure US20140179670A1-20140626-C00661
         		Me 9 2.93 650
    165
    Figure US20140179670A1-20140626-C00662
         		Me 9 0.72 592
    166
    Figure US20140179670A1-20140626-C00663
         		Me 9 0.70 578
    167
    Figure US20140179670A1-20140626-C00664
         		Me 9 2.97 664
    168
    Figure US20140179670A1-20140626-C00665
         		Me 9 0.81 606
    169
    Figure US20140179670A1-20140626-C00666
         		Me 9 0.68 592
    170
    Figure US20140179670A1-20140626-C00667
         		Me 9 0.91 563
    171
    Figure US20140179670A1-20140626-C00668
         		Me 9 1.06 678
    172
    Figure US20140179670A1-20140626-C00669
         		Me 9 0.70 578
    173
    Figure US20140179670A1-20140626-C00670
         		Et 9 0.90 579
    174
    Figure US20140179670A1-20140626-C00671
         		Et 9 0.84 593
    175
    Figure US20140179670A1-20140626-C00672
         		Me 9 0.87 534
    176
    Figure US20140179670A1-20140626-C00673
         		Et 9 0.84 567
    177
    Figure US20140179670A1-20140626-C00674
         		Et 9 0.8 597
    178
    Figure US20140179670A1-20140626-C00675
         		Me 226 9 0.87 553
    179
    Figure US20140179670A1-20140626-C00676
         		Me 9 0.9 535
    • Example 180
  • Figure US20140179670A1-20140626-C00677
  • To 1-(4-cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide (prepared in example 143) (500 mg) was added DMSO (1.2 ml) and the resulting mixture was stirred at 90° C. for one hour and at room temperature for six hours. The formed crystals were collected by filtering with DMSO to afford 1-(4-cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide DMSO solvate (240 mg).
  • 1H-NMR (CD3OD: 300 MHz) δ: 1.27-1.37 (m, 6H), 1.68 (s, 1.5H), 1.73 (s, 1.5H), 2.65 (s, 6H), 4.90-5.03 (m, 1H), 7.61-7.91 (m, 8H), 8.28 (d, 1H, J=0.6 Hz).
    • Examples 181-186
  • The atropisomers of the compounds prepared in Examples 143, 148 and 360 (20 mg respectively) were resolved on chiral column to afford the compounds indicated in the below-mentioned table (Examples 181-186).
  • Figure US20140179670A1-20140626-C00678
  • [Resolution Condition]
  • Detector: SPD-6A (manufactured by SHIMAZU CO.)
  • HPLC: LC-6A (manufactured by SHIMAZU CO.)
  • Column: CHIRALCEL OD-H (manufactured by DAICEL CO.) (S-5 μm, 20×250 mm)
  • Elution condition:
  • 0.0-60.0 (minute); A/B=1:1
  • Flow rate: 5.0 ml/minute
  • UV: 254 nm
  • Column temperature: 25° C.
  • (with the proviso that the compounds of Examples 185-186 were separated on CHIRAL FLASH IC)
  • TABLE 56
    Retention
    time (min.)/
    Ex. R1 R2 Solvent Yield (mg)
    181 Me CONH2 n-hexane/ 16.2/2.2 57.3/2.7
    182 isopropanol = 1/1
    183 i-Pr CONH2 n-hexane/ 16.4/4.3 29.2/1.6
    184 isopropanol = 1/1
    185 Me Cl n-hexane/ethyl 12.9/3.8 25.3/4.0
    186 acetate = 2/1
    • Example 187
  • Figure US20140179670A1-20140626-C00679
  • To a solution of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (prepared in Example 132) (153 mg) in acetonitrile (5 ml) was added 4-dimethylaminobutanol (0.21 ml), 1-hydroxy-7-azabenzotriazole (126 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg) and the resulting mixture was stirred at room temperature for sixteen hours. To the reaction solution were added saturated aqueous sodium hydrogen carbonate solution (10 ml) and ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-(dimethylamino)butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate (137 mg). UPLC/MS 595 (M+H)/0.73 min (measurement condition 9)
    • Examples 188-190
  • The compounds indicated in the below-mentioned table (Examples 188-190) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 187.
  • Figure US20140179670A1-20140626-C00680
  • TABLE 57
    Measurement
    Ex. R cond. (LC-MS: Rt/[M + H]+)
    188
    Figure US20140179670A1-20140626-C00681
         		9 0.98 510
    189
    Figure US20140179670A1-20140626-C00682
         		9 1.03 524
    190
    Figure US20140179670A1-20140626-C00683
         		9 0.876 540
    • Example 191
  • Figure US20140179670A1-20140626-C00684
  • To a suspension of the compound prepared in Example 1 (2.0 g) in acetonitrile (20 ml) was added concentrated sulfuric acid (1.08 ml) and the resulting mixture was stirred with heating under reflux for three hours. The reaction mixture was cooled to room temperature and thereto were added water (40 ml) and ethyl acetate (40 ml×1, 20 ml×1) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue was added chloroform (10 ml) and the resulting mixture was stirred at 60° C. for thirty minutes. The mixture was stirred at room temperature overnight and the precipitated crystals were collected by filtration and washed with chloroform to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (2.06 g).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 1.78 (s, 1.5H), 1.79 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (s, 1.5H), 7.52-7.60 m, 1H), 7.69-7.74 (m, 2H), 7.81-7.86 (m, 2.5H), 7.89-7.92 (m, 3H), 8.02 (s, 0.5H).
  • UPLC/MS 532 (M+H)/0.73 min. (measurement condition 9)
    • Examples 192-194
  • The compounds indicated in the below-mentioned table (Examples 192-194) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in the Example 191.
  • Figure US20140179670A1-20140626-C00685
  • TABLE 58
    Measurement (LC-MS: Rt/
    Ex. R1 R2 cond [M + H]+)
    192 i-Pr Me 9 560 0.77
    193 Et Me 9 546 0.70
    194 Me Et 9 546 0.75
    • Examples 195-196
  • Figure US20140179670A1-20140626-C00686
    • Step 1 Example 195
  • The 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 191) (20.0 g) was dissolved in methanol (300 ml) and the mixture was concentrated under reduced pressure. Thereto were added (−)-cis-2-benzylaminocyclohexane methanol (8.3 g) and ethyl acetate (200 ml), and the resulting mixture was stirred with heating under reflux for two hours and then stirred at room temperature for fifteen hours. The precipitated solids were collected by filtration and washed with ethyl acetate to afford crude crystals (11.5 g, optical purity 35.3% de). The obtained crude crystals were dissolved in methanol (100 ml) and then concentrated under reduced pressure, and thereto was added ethyl acetate (100 ml) and the resulting mixture was stirred with heating under reflux for one hour and stirred at room temperature for fifteen hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to afford (−)-cis-2-benzylaminocyclohexane methanol salt of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (4.2 g, optical purity 99.4% de. late eluting peak).
  • 1H-NMR (CD3OD: 300 MHz) δ: 1.40-1.60 (m, 4H), 1.78-1.87 (m, 7H), 2.38-2.44 (m, 1H), 3.24 (s, 1.5H), 3.25 (s, 1.5H), 3.32-3.39 (m, 1H), 3.74 (dd, 1H, J=10.8, 4.4 Hz), 4.05-(dd, 1H, J=10.8, 9.2 Hz), 4.15 (d, 1H, J=13.0 Hz), 4.38 (d, 1H, J=13.0 Hz), 7.40-7.47 (m, 5H), 7.49-7.96 (m, 6H), 8.02 (s, 1H).
    • Step 2 Example 196
  • To the crystals obtained in Example 195 were added ethyl acetate (50 ml) and 5 N hydrochloric acid (10 ml) followed by an addition of ethyl acetate (50 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyridin-5-yl)-1H-pyrazole-4-sulfonic acid (2.7 g, optical purity 99.3% ee, late eluting peak).
  • [α]D 25=70.36, c 0.122, MeOH
  • UPLC/MS 532 (M+H)/0.73 min. (measurement condition 9)
    • [Analysis Condition of Examples 195 and 196 and the Others]
  • UPLC: ACQUITY UPLC (trade mark, manufactured by Waters Corp.)
  • Detector: PDA detector, manufactured by Waters Corp.)
  • Column: CHIRALPAK IC (manufactured by Daicel Corp.) (S-5 μm, 4.6×250 mm)
  • Flow rate: 1.0 ml/min
  • Detection wavelength: 254 nm
  • Mobile phase: 0.1% TFA/MeOH
  • Elution condition: 15 min.
  • Early eluting peak: 7.198 (min.)
  • Late eluting peak: 8.299 (min.)
    • Example 197
  • The compound of Example 195 was also prepared according to the below-mentioned processes.
  • Figure US20140179670A1-20140626-C00687
  • A solution of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 191) (36.0 g) and (−)-cis-2-benzylaminocyclohexanemethanol (14.9 g) in methanol (360 ml) was stirred for one hour with heating under reflux. The reaction mixture was concentrated under reduced pressure and thereto was added methanol (15.0 ml). The mixture was stirred at 80° C. and thereto was added ethyl acetate (360 ml) and the mixture was stirred for one and a half hours and then stirred at room temperature for fifteen hours. The precipitated solids were collected by filtration and washed with ethyl acetate to afford the same product as that of Example 197, (−)-cis-2-benzylaminocyclohexanemethanol salt of (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (16.6 g, optical purity 99.4% de, late eluting peak).
    • Examples 198-199
  • Figure US20140179670A1-20140626-C00688
    • Step 1 Example 198
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 191 (7.2 g) and quinine (4.4 g) were dissolved in methanol (12 ml) and the resulting mixture was stirred with heating under reflux for fifteen minutes, at room temperature for one hour and at 0° C. for four hours. The precipitated solids were collected by filtration and washed with isopropanol to afford quinine salt of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (3.6 g, optical purity>99.8% de, early eluting peak).
  • 1H-NMR (CD3OD: 300 MHz) δ: 1.57-1.65 (m, 1H), 1.77 (s, 1.5H), 1.81 (s, 1.5H), 1.90-1.95 (m, 1H), 2.09-2.26 (m, 3H), 2.77-(brs, 1H), 3.22-3.32 (m, 6H), 3.54-3.62 (m, 2H), 4.01 (s, 3H), 4.17 (brs, 1H), 5.02-5.15 (m, 2H), 5.74-5.87 (m, 2H), 7.38 (d, 1H, J=2.6 Hz), 7.49 (dd, 1H, J=9.3, 2.7 Hz), 7.57-7.88 (m, 9H), 7.94-8.03 (m, 2H), 8.72 (d, 1H, J=4.6 Hz).
    • Step 2 Example 199
  • To a crystal prepared in Example 200 (2.0 g) were added ethyl acetate (30 ml) and 5 N hydrochloric acid (5 ml) followed by an addition of ethyl acetate (30 ml×3) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford (−)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (1.2 g, optical purity>99.8% ee, early eluting peak). UPLC/MS 532 (M+H)/0.73 min. (measurement condition 9)
  • The optical resolution for the compound of Example 198 can be also carried out by using chiral amine indicated in the below-mentioned table other than quinine (Examples 200-203).
  • TABLE 59
    Ex. Chiral amine Solvent
    200 cinchonine MeOH
    201 cinchonidine MeOH/IPA
    202 (+)-cis-2- IPA
    benzylaminocyclohexane
    methanol
    203 (1S,2S)-(−)-2-amino-1- AcOEt
    phenyl-1,3-propanediol
    • Examples 204-205
  • Figure US20140179670A1-20140626-C00689
    • Step 11 Example 204
  • To a suspension of the compound prepared in Example 191 (10.0 g) in acetonitrile (70 ml) was added phosphorus oxychloride (7.04 ml) and the resulting mixture was stirred at 90° C. for two hours. The mixture was concentrated on evaporator instrument under reduced pressure and to the residue were then added ethyl acetate (50 ml) and hexane (50 ml) and the mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with ethyl acetate/hexane=1/1 to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonylchloride (10.3 g). UPLC/MS 550 (M+H)/1.08 min. (measurement condition 9).
    • Step 2 Example 205
  • A suspension of the compound prepared in Example 204 (50.0 mg) in acetonitrile (20 ml) was cooled to 0° C. and thereto was added ammonia water (28%, 5.0 ml) dropwise and the mixture was stirred for another ten minutes. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (42.0 mg).
  • UPLC/MS 531 (M+H)/0.93 min. (measurement condition 9)
    • Examples 206-208
  • The compound indicated in the below-mentioned table (Examples 206-208) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Examples 204 and 305.
  • Figure US20140179670A1-20140626-C00690
  • TABLE 60
    melting point Measurement (LC-MS:
    Ex. R1 R2 (m.p.) cond. Rt/[M + H]+)
    206 i-Pr Me 9 559 0.97
    207 Et Me 195 9 545 0.91
    208 Me Et 9 545 0.94
    • Example 209
  • Figure US20140179670A1-20140626-C00691
  • To a suspension of (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 196) (2.67 g) in acetonitrile (20 ml) were added pyridine (0.81 ml) and phosphorus oxychloride (1.87 ml) and the resulting mixture was stirred at room temperature for forty five minutes. Without an isolation of the formed 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonyl chloride, the reaction solution was added dropwise to ammonia water (28%, 20 ml) that cooled to 0° C. and the resulting mixture was stirred for ten minutes. To the reaction solution were added water (40 ml) and ethyl acetate (40 ml×2) such that the intended products were extracted into an organic layer. The organic layer washed with 4% ammonia water (20 ml), saturated saline (8 ml), 1N hydrochloric acid (20 ml×2) and saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (2.33 g). UPLC/MS 531 (M+H)/0.93 min. (measurement condition 9)
    • Examples 210-211
  • Figure US20140179670A1-20140626-C00692
    • Step 1 Examples 210
  • To a suspension of (−)-cis-2-benzylaminocyclohexanemethanol salt of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 195) (6.83 g) in acetonitrile (48 ml) were added pyridine (1.47 ml) and phosphorus oxychloride (3.39 ml) and the resulting mixture was stirred at room temperature for two hours. The reaction solution was added dropwise to ammonia water (28%, 48 ml) that cooled to 0° C. and the mixture was stirred for another ten minutes. To the reaction solution were added water (50 ml) and ethyl acetate (100 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with 4% ammonia water (50 ml), saturated saline (20 ml), 1N hydrochloric acid (50 ml×2) and saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the same product as Example 209, (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (4.84 g). UPLC/MS 531 (M+H)/0.93 min. (measurement condition 9)
    • Step 2 Example 211
  • (+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 210) (331 mg) was recrystallized from isopropanol (IPA) to afford (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide 0.5 IPA solvates (299 mg) ([α]D 24=276.4, c 0.109, CHCl3)
  • 1H-NMR (DMSO-d6: 300 MHz) δ: 1.02 (d, 3H, J=6.0 Hz), 1.64-(s, 1.5H), 1.68 (s, 1.5H), 3.12 (s, 1.5H), 3.14 (s, 1.5H), 3.73-3.79 (0.5H, m), 4.43 (d, 0.5H, J=4.2 Hz), 7.49 (brs, 2H), 7.66-7.72 (m, 3H), 7.78-7.84 (m, 2H), 7.91-8.00 (m, 4H), 8.14 (s, 1H)
    • Example 212
  • Figure US20140179670A1-20140626-C00693
  • To a suspension of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid chloride (prepared in Example 204) (2.05 g) in chloroform (60 ml) were added (S)-2-phenylglycinol (767 mg) and diisopropylethylamine (0.99 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure and thereto were added 1N hydrochloric acid (30 ml) and ethyl acetate (60 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (813 mg).
  • UPLC/MS 651 (M+H)/0.98 min. (measurement condition 9)
    • Example 213
  • Figure US20140179670A1-20140626-C00694
  • (+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 209) (49 mg) was dissolved in acetonitrile (1 ml) and thereto were added trimethylacetic anhydride (0.086 ml) and concentrated sulfuric acid (0.01 ml) and the resulting mixture was stirred at 60° C. for ten minutes. The mixture was cooled to room temperature, and thereto were water (30 ml) and ethyl acetate (30 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate). The mixture was concentrated, and thereto were added chloroform (0.5 ml) and hexane (2 ml) and the mixture was stirred for one hour. The precipitated solids were collected by filtration and washed with chloroform/hexane=1/4 to afford N-(1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-4-ylsulfonyl)pivalamine (48 mg).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 1.04 (s, 9H), 1.51 (s, 1.5H), 1.64 (s, 1.5H), 3.13 (s, 1.5H), 3.18 (s, 1.5H), 7.64-7.66 (m, 0.5H), 7.70-7.74 (m, 2H), 7.78-7.86 (m, 2H), 7.91-8.00 (m, 4H), 8.28-8.30 (m, 0.5H), 11.54 (s, 1H).
  • UPLC/MS 615 (M+H)/1.16 min. (measurement condition 9)
    • Example 214
  • Figure US20140179670A1-20140626-C00695
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 205) (99 mg) was dissolved in acetone (8 ml) and thereto were added butyl chloroformate (0.036 ml) and potassium carbonate (52 mg) and the mixture was stirred at 60° C. for fifteen hours. The mixture was cooled to room temperature, and to the reaction solution were added 1N hydrochloric acid (20 ml) and ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-4-ylsulfonyl)carbamate (100 mg).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 0.80 (t, 1.5H, J=7.4 Hz), 0.82 (t, 1.5H, J=7.3 Hz), 1.17-1.27 (m, 2H), 1.41-1.49 (m, 2H), 1.60 (s, 1.5H), 1.66 (s, 1.5H), 3.14 (s, 1.5H), 3.16 (s, 1.5H), 3.90-3.98 (m, 2H), 7.70-7.74 (m, 2.5H), 7.81-7.95 (m, 3H), 7.99-8.01 (m, 2.5H), 8.29-8.31 (m, 1H), 11.88 (s, 0.5H), 11.92 (s, 0.5H). UPLC/MS 631 (M+H)/1.07 min. (measurement condition 9)
    • Example 215
  • Figure US20140179670A1-20140626-C00696
  • (+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 209) (46 mg) was dissolved in acetonitrile (1 ml) and thereto were added benzoic acid (13 mg), 4-dimethylaminopyridine (21 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg) and the resulting mixture was stirred for three hours at room temperature. To the reaction solution were added 1N hydrochloric acid (20 ml) and ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (20 ml) and saturated saline (30 ml) successively, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford N-(1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-4-ylsulfonyl)benzamide (51 mg).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 1.55 (s, 3H), 3.02 (s, 1.5H), 3.04 (s, 1.5H), 7.25-7.50 (m, 4H), 7.68-7.78 (m, 4H), 7.82-7.95 (m, 6H), 8.15-8.17 (m, 1H), 12.46 (s, 1H).
  • UPLC/MS 635 (M+H)/1.02 min. (measurement condition 9)
    • Example 216
  • Figure US20140179670A1-20140626-C00697
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 205) (97 mg) was dissolved in acetonitrile (2 ml) and thereto were added ethyl isocyanate (0.043 ml) and diisopropylethylamine (0.065 ml) and the resulting mixture was stirred at 50° C. for four hours. The mixture was cooled to room temperature, and thereto were then added 1N hydrochloric acid (20 ml) and ethyl acetate (30 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (20 ml) and saturated saline (30 ml) successively, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(ethylcarbonyl)-1H-pyrazole-4-sulfonamide (88 mg).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 0.86 (t, 1.5H, J=7.1 Hz), 0.91 (t, 1.5H, J=7.2 Hz), 1.49 (s, 1.5H), 1.58 (s, 1.5H), 2.87-3.00 (m, 2H), 3.16 (s, 1.5H), 3.19 (s, 1.5H), 6.30-6.33 (m, 1H), 7.68-7.83 (m, 4H), 7.89-7.92 (m, 2H), 7.98-8.02 (m, 2H), 8.25-8.27 (m, 2H), 10.79 (s, 1H).
  • UPLC/MS 602 (M+H)/0.93 min. (measurement condition 9)
    • Examples 217-259
  • The compounds indicated in the below-mentioned table (Examples 217-259) were obtained by using the corresponding starting materials (racemates, optical isomers) according to the similar reaction and methods to those described in Examples 204-205 and 212-216.
  • Figure US20140179670A1-20140626-C00698
  • TABLE 61
    Optical activity
    of product
    r: racemate,
    e: eutomer Measurement
    Ex. R R1 d: distomer cond. (LC-MS: Rt/[M + H]+)
    217 NHMe Me r 9 0.93 545
    218 NHMe Me e 9 0.93 545
    219 NMe2 Me r 9 1.03 559
    220
    Figure US20140179670A1-20140626-C00699
         		Me r 9 1.08 585
    221
    Figure US20140179670A1-20140626-C00700
         		Me r 9 1.04 601
    222
    Figure US20140179670A1-20140626-C00701
         		Me r 9 0.913 616
    223
    Figure US20140179670A1-20140626-C00702
         		Me r 9 0.758 643
    224
    Figure US20140179670A1-20140626-C00703
         		Me r 9 1.093 715
    225
    Figure US20140179670A1-20140626-C00704
         		Me r 9 0.876 615
    226
    Figure US20140179670A1-20140626-C00705
         		Me r 9 0.893 643
    227
    Figure US20140179670A1-20140626-C00706
         		Me e 9 0.86 575
    228
    Figure US20140179670A1-20140626-C00707
         		Me e 9 1.04 674
    229
    Figure US20140179670A1-20140626-C00708
         		Me r 9 0.855 617
    230
    Figure US20140179670A1-20140626-C00709
         		Me r 9 0.723 616
    231
    Figure US20140179670A1-20140626-C00710
         		Me r 9 0.967 604
    232
    Figure US20140179670A1-20140626-C00711
         		Me r 9 0.738 659
  • TABLE 62
    233
    Figure US20140179670A1-20140626-C00712
         		Me e 9 1.09 665
    234
    Figure US20140179670A1-20140626-C00713
         		Me d 9 1.08 665
    235
    Figure US20140179670A1-20140626-C00714
         		Et e 9 1.130 679
    236
    Figure US20140179670A1-20140626-C00715
         		Et d 9 1.129 679
    237
    Figure US20140179670A1-20140626-C00716
         		Me r 9 1.28 713
    238
    Figure US20140179670A1-20140626-C00717
         		Me e 9 0.98 651
    239
    Figure US20140179670A1-20140626-C00718
         		Me e 9 0.97 601
    240
    Figure US20140179670A1-20140626-C00719
         		Me e 9 1.09 644
    241
    Figure US20140179670A1-20140626-C00720
         		Me e 9 0.90 601
    242
    Figure US20140179670A1-20140626-C00721
         		Me r 9 0.92 573
    243
    Figure US20140179670A1-20140626-C00722
         		Me e 9 1.05 615
    244
    Figure US20140179670A1-20140626-C00723
         		Me r 9 1.05 615
    245
    Figure US20140179670A1-20140626-C00724
         		Et r 9 1.07 629
    246
    Figure US20140179670A1-20140626-C00725
         		Me r 9 0.99 601
    247
    Figure US20140179670A1-20140626-C00726
         		Me r 9 1.08 641
    248
    Figure US20140179670A1-20140626-C00727
         		Me e 9 1.08 641
    249
    Figure US20140179670A1-20140626-C00728
         		Me e 9 1.02 635
    250
    Figure US20140179670A1-20140626-C00729
         		Me e 9 1.02 653
  • TABLE 63
    251
    Figure US20140179670A1-20140626-C00730
         		Me e 9 1.06 669
    252
    Figure US20140179670A1-20140626-C00731
         		Me r 9 0.95 589
    253
    Figure US20140179670A1-20140626-C00732
         		Me r 9 1.07 631
    254
    Figure US20140179670A1-20140626-C00733
         		Me r 9 1.05 575 (- t-Bu)
    255
    Figure US20140179670A1-20140626-C00734
         		Me e 9 1.16 615
    256
    Figure US20140179670A1-20140626-C00735
         		Me r 9 0.93 602
    257
    Figure US20140179670A1-20140626-C00736
         		Me e 9 0.91 602
    258
    Figure US20140179670A1-20140626-C00737
         		Me r 9 0.90 602
    259
    Figure US20140179670A1-20140626-C00738
         		Me e 9 1.10 657
  • The NMR data of Examples 243 and 248 are shown below.
    • Example 243
  • Figure US20140179670A1-20140626-C00739
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 0.79 (t, 1.5H, J=7.4 Hz), 0.82 (t, 1.5H, J=7.3 Hz), 1.16-1.24 (m, 2H), 1.35-1.42 (m, 2H), 1.54 (s, 1.5H), 1.63 (s, 1.5H), 2.08-2.17 (m, 2H), 3.16 (s, 1.5H), 3.18 (s, 1.5H), 7.60-7.66 (m, 0.5H), 7.70-7.75 (m, 2H), 7.78-7.86 (m, 2H), 7.92-7.95 (m, 1.5H), 7.98-8.02 (m, 2H), 8.29-8.31 (m, 1H), 11.87 (s, 1H).
    • Example 248
  • Figure US20140179670A1-20140626-C00740
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 1.07-1.24 (m, 5H), 1.51 (s, 1.5H), 1.55-1.74 (m, 5H), 1.63 (s, 1.5H), 1.98-2.06 (m, 1H), 3.15 (s, 1.5H), 3.19 (s, 1.5H), 7.62-7.66 (m, 0.5H), 7.70-7.73 (m, 2H), 7.74-7.86 (m, 2H), 7.95-7.98 (m, 1.5H), 7.98-8.02 (m, 2H), 8.29-8.31 (m, 1H), 11.76 (s, 0.5H), 11.82 (s, 0.5H).
    • Example 260
  • Figure US20140179670A1-20140626-C00741
  • The compound prepared in Example 243 (131 mg) was dissolved in THF (2.6 ml) and thereto was added 5N aqueous sodium hydroxide solution (0.045 ml) and the mixture was stirred at room temperature for fifteen minutes. The solvent was distilled under reduced pressure on evaporator instrument to afford sodium salt compound (135 mg).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 0.77 (t, 1.5H, J=7.2 Hz), 0.79 (t, 1.5H, J=7.2 Hz), 1.14-1.19 (m, 2H), 1.30-1.35 (m, 2H), 1.66 (s, 1.5H), 1.73 (s, 1.5H), 1.85-1.92 (m, 2H), 3.11 (s, 1.5H), 3.13 (s, 1.5H), 7.58-7.61 (m, 0.5H), 7.68-7.73 (m, 2.5H), 7.81-7.87 (m, 1.5H), 7.91-7.98 (m, 4.5H).
  • UPLC/MS 615 (M+H)/1.04 min. (measurement condition 9)
    • Example 261
  • The below-mentioned compound was obtained according to the similar process to those of Example 260.
  • Figure US20140179670A1-20140626-C00742
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 1.05-1.21 (m, 5H), 1.23 (s, 1.5H), 1.50-1.85 (m, 6H), 1.73 (s, 1.5H), 3.11 (s, 1.5H), 3.13 (s, 1.5H), 7.57-7.61 (m, 0.5H), 7.67-7.74 (m, 2.5H), 7.80-7.87 (m, 1.5H), 7.92-8.02 (m, 4.5H).
  • UPLC/MS 641 (M+H)/1.08 min (measurement condition 9)
    • Example 262
  • Figure US20140179670A1-20140626-C00743
  • To (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (prepared in Example 212) (813 mg) was added in water bath (at 20° C.) concentrated sulfuric acid (30 ml) and the resulting mixture was stirred for fifteen minutes. The mixture was cooled to 0° C. and to the reaction solution was then added water (60 ml) dropwise followed by an addition of chloroform (50 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford the same product as Example 209, (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (406 mg).
  • 1H-NMR (DMSO-d6: 400 MHz) δ: 1.65 (s, 1.5H), 1.69 (s, 1.5H), 3.12 (s, 1.5H), 3.14 (s, 1.5H), 7.51 (brs, 2H), 7.66-7.72 (m, 2.5H), 7.78-7.84 (m, 2H), 7.91-8.00 (m, 3.5H), 8.15 (s, 1H).
  • UPLC/MS 531 (M+H)/0.87 min. (measurement condition 9)
    • Example 263
  • Figure US20140179670A1-20140626-C00744
  • To the compound prepared in Example 233 (1.10 g) was added at room temperature trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature for fifteen minutes. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the same product as Example 209, (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (896.1 mg).
    • Example 264
  • The below-mentioned compound was obtained by using the compound of Example 235 according to the similar reaction and treatment method to those described in Example 263.
  • Figure US20140179670A1-20140626-C00745
  • (+)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide
  • 1H-NMR (CDCl3: 300 MHz) δ: 1.23-1.28 (m, 3H), 1.34 (d, 3H, J=6.6 Hz), 4.04 (d, 3H, J=7.2 Hz), 7.02 (d, 0.5H, J=8.1 Hz), 7.09 (s, 0.5H), 7.48-7.66 (m, 4H), 7.71 (d, 1H, J=7.8 Hz), 7.78-7.82 (m, 2H), 8.14 (s, 1H).
  • UPLC/MS 545 (M+H)/0.93 min (measurement condition 9), [α]D 24=100.32, c 0.261, CHCl3.
    • Example 265
  • Figure US20140179670A1-20140626-C00746
  • The solution of the compound prepared in Example 204 (55 mg) in tetrahydrofuran (20 ml) was added at 0° C. to an aqueous solution of sodium sulfite (25 mg) and sodium hydrogen carbonate (25 mg) in water (1.0 ml) and the resulting mixture was stirred at the same temperature for one hour. To the reaction solution was then added methyl iodide (142 mg) and the resulting mixture was stirred at 25° C. for fifty hours. The reaction solution was concentrated under reduced pressure and thereto were then added water (10 ml) and ethyl acetate (10 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile (58 mg). UPLC/MS 530 (M+H)/0.97 min. (measurement condition 9)
    • Examples 266-267
  • Figure US20140179670A1-20140626-C00747
    • Step 1 Example 266
  • To a suspension of (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid (prepared in Example 196) (315 mg) in acetonitrile (2.2 ml) were added pyridine (94 mg) and phosphorus oxychloride (365 mg) and the resulting mixture was stirred at room temperature for thirty minutes. To the reaction mixture was added water (5 ml) followed by an addition of ethyl acetate (10 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid chloride (330 mg).
  • UPLC/MS 550 (M+H)/1.08 min (measurement condition 9)
    • Step 2 Example 267
  • A solution of the compound prepared in Example 266 (1.78 g) in tetrahydrofuran (30 ml) was added at 0° C. to an aqueous solution of sodium sulfite (774 mg) and sodium hydrogen carbonate (774 mg) in water (15 ml) and the resulting mixture was stirred at the same temperature for one hour. To the reaction solution was then added methyl iodide (4.4 g) and the resulting mixture was stirred at 25° C. for twenty hours. The reaction solution was concentrated under reduced pressure, and thereto were then added water (10 ml) and ethyl acetate (50 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (+)-4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile (1.25 g, [α]D 24=243.76, c 0.119, CHCl3).
  • UPLC/MS 530 (M+H)/0.97 min. (measurement condition 9)
    • Examples 268-269
  • Figure US20140179670A1-20140626-C00748
    • Step 1 Example 268
  • 4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-iodo-1H-pyrazol-1-yl)benzonitrile was obtained by using the compound prepared in Example 1 according to the similar reaction and treatment method to those described in Example 101. UPLC/MS 578 (M+H)/1.07 min. (measurement condition 9)
    • Step 2 Example 269
  • To a solution of 4-(5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-iodo-1H-pyrazol-1-yl)benzonitrile (prepared in Example 268) (98.1 mg) in N,N-dimethy formamide (1.0 ml) were added palladium dibenzylidene acetone complex (15.9 mg), 1,1′-bis(diphenylphosphino)ferrocene) (18.9 mg), N,N-diisopropylethylamine (33.8 μl) and sodium methanethiolate (13.4 mg) and the resulting mixture was stirred at 110° C. for four hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylthio)-1H-pyrazol-1-yl)benzonitrile (57.4 mg).
  • UPLC/MS 498 (M+H)/1.04 min. (measurement condition 9)
    • Example 270
  • Figure US20140179670A1-20140626-C00749
  • To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylthio)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 269) (57.4 mg) in acetic acid (1.0 ml) were added aqueous hydrogen peroxide solution (63.4 μl) and sodium tungstate (3.8 mg) and the resulting mixture was stirred at room temperature for four hours. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (1 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate (50 ml) and then washed with saturated saline (20 ml) and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile (29.4 mg).
  • UPLC/MS 530 (M+H)/0.97 min. (measurement condition 9)
    • Examples 271-274
  • The compounds indicated in the below-mentioned table (Examples 271-274) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Examples 269 and 270.
  • Figure US20140179670A1-20140626-C00750
  • TABLE 64
    Measure-
    ment (LC-MS: Rt/
    Ex. R2 cond. [M + H]+)
    271
    Figure US20140179670A1-20140626-C00751
         		9 0.94 542
    272
    Figure US20140179670A1-20140626-C00752
         		9 0.72 582
    273
    Figure US20140179670A1-20140626-C00753
         		9 0.88 574
    274
    Figure US20140179670A1-20140626-C00754
         		9 0.72 614
    • Example 275
  • Figure US20140179670A1-20140626-C00755
  • To a solution of the compound prepared in Example 269 (2.84 g) in dimethyl sulfoxide (9.8 ml) were added methanesulfinic acid sodium (2.00 g), copper trifluoromethanesulfonate benzene complex (1.24 g), N,N-dimethylethylenediamine (529 mg) and the resulting mixture was stirred at 110° C. for seven hours. The reaction mixture was diluted with ethyl acetate (300 ml), and the organic layer was washed with 10% ammonia water (50 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile (1.25 g).
  • 1H-NMR (CDCl3: 300 MHz) δ: 1.51 (d, 3H, J=11.7 Hz), 3.12 (d, 3H, J=6.0 Hz), 3.40 (d, 3H, J=2.7 Hz), 7.18 (d, 0.5H, J=8.4 Hz), 7.31 (s, 0.5H), 7.46 (d, 0.5H, J=7.5 Hz), 7.53-7.61 (m, 3H), 7.65 (t, 0.5H, J=3.6 Hz), 7.73 (d, 1H, J=7.8 Hz), 7.80 (dd, 2H, J=3.6, 6.0 Hz), 8.18 (d, 1H, J=0.3 Hz).
    • Example 276
  • The below-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 275.
  • Figure US20140179670A1-20140626-C00756
  • (±)-4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile
  • UPLC/MS 558 (M+H)/1.03 (measurement condition 9)
    • Examples 277-286
  • Figure US20140179670A1-20140626-C00757
    Figure US20140179670A1-20140626-C00758
    • Step 1 Example 277
  • The iodide product prepared in Example 269 (1.0 g) was performed the similar reaction and treatment method to those described in Example 269 using the corresponding zinc bromide reagent to afford the acetal product (467 mg). UPLC/MS 538 (M+H)/0.968 min. (measurement condition 9)
    • Example 278
  • The below-mentioned compound was prepared by using the corresponding zinc bromide reagent according to the similar process to those of Example 277.
  • Figure US20140179670A1-20140626-C00759
  • UPLC/MS 552 (M+H)/1.001 min.
    • Step 2 Example 279
  • A solution of the compound prepared in Example 277 (467 mg) and 10% hydrochloric acid (9.0 ml) in THF (9.0 ml) was stirred at room temperature for one and a half hours. To the reaction mixture was added water (10 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the aldehyde product (429 mg).
  • UPLC/MS 494 (M+H)/0.995 min. (measurement condition 9)
    • Example 280
  • The below-mentioned compound was prepared according to the similar process to those of Example 279.
  • Figure US20140179670A1-20140626-C00760
  • UPLC/MS 508 (M+H)/1.007 min. (measurement condition 9)
    • Step 3 Example 281
  • To a solution of the compound prepared in Example 279 (429 mg) and sodium hydrogenphosphate (474 mg) in acetonitrile/water (5.0 ml/5.0 ml) was added at 0° C. sodium chlorite (315 mg) and the resulting mixture was stirred for twenty minutes. To the reaction mixture were added 10% aqueous sodium thiosulfate solution (10 ml) and 10% hydrochloric acid (10 ml) followed by an addition of ethyl acetate (10 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml). dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol) to afford the carboxylic acid product (207 mg).
  • UPLC/MS 510 (M+H)/0.913 min. (measurement condition 9)
    • Example 282
  • The below-mentioned compound was prepared according to the similar process to those of Example 279.
  • Figure US20140179670A1-20140626-C00761
  • UPLC/MS 524 (M+H)/0.937 min. (measurement condition 9)
    • Step 4
  • The compounds indicated in the below-mentioned table (Examples 283-286) were obtained by using the carboxylic acid products prepared in Examples 281 and 282 according to the similar reaction and treatment method to those of Example 75.
  • Figure US20140179670A1-20140626-C00762
  • TABLE 65
    Measurement
    Ex. R n m.p. cond. (LC-MS: Rt/[M + H]+)
    283 NH2 1 251 9 0.86 509
    284 NMe2 1 9 0.93 537
    285 NH2 2 242 9 0.87 523
    286 NMe2 2 9 0.96 551
    • Examples 287-288
  • Figure US20140179670A1-20140626-C00763
    • Step 1 Example 287
  • The above-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 101. UPLC/MS 592 (M+H)/1.11 min. (measurement condition 9)
    • Step 2 Example 288
  • To a solution of the compound prepared in Example 287 (401.2 mg) in tetrahydrofuran (1.0 ml) was added at −78° C. a solution of isopropyl magnesium chloride-lithium chloride complex (1.3 M tetrahydrofuran solution, 0.78 ml) followed by an addition of acetone (150 μl) and the resulting mixture was stirred at −78° C. for five hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 ml) followed by an addition of ethyl acetate (30 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzonitrile (114.7 mg).
  • UPLC/MS 52 4 (M+H)/0.95 min. (measurement condition 9)
  • The compounds indicated in the below-mentioned table (Examples 289-293) were obtained by using the corresponding starting materials and treatment method to those described in Example 288. On the other hand, the compound of Example 293 was prepared by using the compound of Example 290 according to the similar process to those of Example 271.
  • Figure US20140179670A1-20140626-C00764
  • TABLE 66
    Measurement (LC-MS: Rt/
    Ex. R2 R1 cond. [M + H]+)
    289
    Figure US20140179670A1-20140626-C00765
         		Et 9 1.00  536
    290
    Figure US20140179670A1-20140626-C00766
         		Me 9 0.96  568
    291
    Figure US20140179670A1-20140626-C00767
         		Me 9 1.014 623
    292
    Figure US20140179670A1-20140626-C00768
         		Me 9 0.90  510
    293
    Figure US20140179670A1-20140626-C00769
         		Me 9 0.84  600
  • The compounds in below-mentioned table (Examples 294-296) were obtained by using the compound of Example 291 according to the similar reaction and treatment method to those described in Examples 85, 86 and 70.
  • Figure US20140179670A1-20140626-C00770
  • TABLE 67
    Measurement (LC-MS: Rt/
    Ex. R2 cond. [M + H]+)
    294
    Figure US20140179670A1-20140626-C00771
         		9 0.653 294
    295
    Figure US20140179670A1-20140626-C00772
         		9 0.804 295
    296
    Figure US20140179670A1-20140626-C00773
         		9 0.664 296
    • Example 297
  • Figure US20140179670A1-20140626-C00774
  • To a solution of 4-(5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 288) (114.7 mg) in chloroform (1.0 ml) was added at room temperature sodium azide (28.4 mg) and trifluoroacetic acid (200 μl) and the resulting mixture was stirred at room temperature for sixteen hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford the residue. To a solution of the obtained residue in acetic acid (1.0 ml) were added at room temperature zinc dust (143.2 mg) and water (200 μl) and the resulting mixture was stirred at room temperature for eight hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the solids were then filtered, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-(2-aminopropane-2-yl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (51.8 mg). UPLC/MS 523 (M+H)/0.73 min. (measurement condition 9)
    • Example 298
  • The below-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 297.
  • Figure US20140179670A1-20140626-C00775
  • UPLC/MS 535 (M+H)/1.00 min (measurement condition 9)
    • Example 299
  • Figure US20140179670A1-20140626-C00776
  • To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-hydroxymethyl-1H-pyrazol-1-yl)benzonitrile (prepared in Example 138) (1.80 g) in chloroform (50 ml) was added manganese dioxide (9.00 g) and the resulting mixture was stirred at room temperature for thirteen hours. The reaction mixture was filtered through Celite (trade mark) and then concentrated under reduced pressure to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-formyl-1H-pyrazol-1-yl)benzonitrile (1.70 g).
  • UPLC/MS 480 (M+H)/0.95 min. (measurement condition 9)
    • Examples 300-313
  • The compounds indicated in the below-mentioned table (Examples 300-313) were obtained by using the aldehyde product obtained in Example 299 and the corresponding starting materials according to the similar reaction and treatment method to those described in Example 69.
  • Figure US20140179670A1-20140626-C00777
  • TABLE 68
    Measurement (LC-MS: Rt/
    Ex. R cond. [M + H]+)
    300
    Figure US20140179670A1-20140626-C00778
         		9 0.75 552
    301
    Figure US20140179670A1-20140626-C00779
         		9 0.90 559
    302
    Figure US20140179670A1-20140626-C00780
         		9 0.69 537
    303
    Figure US20140179670A1-20140626-C00781
         		9 0.72 551
    304
    Figure US20140179670A1-20140626-C00782
         		9 0.73 552
    305
    Figure US20140179670A1-20140626-C00783
         		9 1.00 557
    306
    Figure US20140179670A1-20140626-C00784
         		9 0.72 536
    307
    Figure US20140179670A1-20140626-C00785
         		9 0.70 552
    308
    Figure US20140179670A1-20140626-C00786
         		9 0.70 552
    309
    Figure US20140179670A1-20140626-C00787
         		9 0.70 566
    310
    Figure US20140179670A1-20140626-C00788
         		9 0.89 600
    311
    Figure US20140179670A1-20140626-C00789
         		9 0.75 628
    312
    Figure US20140179670A1-20140626-C00790
         		9 0.76 629
    313
    Figure US20140179670A1-20140626-C00791
         		9 0.72 593
    • Example 314
  • Figure US20140179670A1-20140626-C00792
  • A solution of 4-(A4-amino(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 140) (200 mg), N-benzyl-bis(2-chloroethyl)amine hydrochloride (576 mg), sodium iodide (322 mg), sodium hydrogen carbonate (181 mg) in NMP (2.0 ml) was stirred at 120° C. for three hours. To the reaction mixture was added water (10 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-(4-benzylpiperidin-1-yl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (97.1 mg). UPLC/MS 626 (M+H)/0.77 min. (measurement condition 9)
    • Example 315
  • The below-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 314.
  • Figure US20140179670A1-20140626-C00793
  • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-morpholino-1H-pyrazol-1-yl)benzonitrile
  • UPLC/MS 537 (M+H)/0.97 min. (measurement condition 9)
    • Example 316
  • The below-mentioned compound was obtained by using 4-(4-(4-benzylpiperidine-1-yl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 314) according to the similar reaction and treatment method to those described in Example 72.
  • Figure US20140179670A1-20140626-C00794
  • 4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-piperazin-1-yl)-1H-pyrazol-1-yl)benzonitrile
  • UPLC/MS 537 (M+H)/0.67 min. (measurement condition 9)
    • Examples 317-318
  • The compounds indicated in the below-mentioned table (Examples 317-318) were obtained by using the compound prepared in Example 316 according to the similar reaction and treatment method to those described in Example 69.
  • Figure US20140179670A1-20140626-C00795
  • TABLE 69
    Measurement
    Ex. R cond. (LC-MS: Rt/[M + H]+)
    317 Me 9 550 (M + H)/0.70 min
    318 i-Pr 9 578 (M + H)/0.72 min
    • Examples 319-328
  • The compounds indicated in the below-mentioned table (Examples 319-328) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Examples 1 and 30.
  • Figure US20140179670A1-20140626-C00796
  • TABLE 70
    Measurement (LC-MS: Rt/
    Ex. R1 R2 cond. m.p. [M + H]+)
    319
    Figure US20140179670A1-20140626-C00797
         		H 9 1.19 641
    320
    Figure US20140179670A1-20140626-C00798
         		H 9 1.19 641
    321
    Figure US20140179670A1-20140626-C00799
         		H 9 1.16 655
    322
    Figure US20140179670A1-20140626-C00800
         		H 9 1.17 655
    323
    Figure US20140179670A1-20140626-C00801
         		H 9 1.17 655
    324
    Figure US20140179670A1-20140626-C00802
         		H 9 1.09 559
    325 H H 9 283  0.883 438
    326 Me F 9 0.95 470
    327 Et F 9 0.99 484
    328 Me Me 9 0.98 466
  • The NMR data of Example 324 is shown below.
  • Figure US20140179670A1-20140626-C00803
  • (R)-2-(5-(1-(4-Cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonamide
  • 1H-NMR (CDCl3: 300 MHz) δ: 1.38 (brs, 3H), 1.55 (d, 3H, J=6.6 Hz), 3.01-3.10 (m, 1H), 4.15-4.25 (m, 1H), 4.83 (brs, 2H), 5.47-5.69 (m, 1H), 6.44-6.46 (m, 1H), 7.40-7.44 (m, 1H), 7.46-7.50 (m, 1H), 7.56-7.64 (m, 3H), 7.66-7.72 (m, 3H), 7.75-7.77 (m, 1H).
    • Example 329
  • Figure US20140179670A1-20140626-C00804
  • To a solution of the compound prepared in Example 319 (584.2 mg) in acetonitrile (5.0 ml) were added at room temperature sodium iodide (683.6 mg), trimethylsilyl chloride (582 μl) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(6-methyl-2,4-dioxo-3-(pyrrolidin-3-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (425.0 mg).
  • UPLC/MS 507 (M+H)/0.84 min. (measurement condition 9)
    • Examples 330-333
  • The compounds indicated in the below-mentioned table (Examples 330-333) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 329.
  • Figure US20140179670A1-20140626-C00805
  • TABLE 71
    Measurement (LC-MS: Rt/
    Ex. R1 cond. [M + H]+)
    330
    Figure US20140179670A1-20140626-C00806
         		9 0.74 507
    331
    Figure US20140179670A1-20140626-C00807
         		9 0.76 521
    332
    Figure US20140179670A1-20140626-C00808
         		9 0.72 522
    333
    Figure US20140179670A1-20140626-C00809
         		9 0.72 522
    • Examples 334-357
  • The compounds indicated in the below-mentioned table (Examples 334-357) were obtained by using the corresponding starting materials according to the similar reaction and treatment method described in Examples 69, 75 and 85.
  • Figure US20140179670A1-20140626-C00810
  • TABLE 72
    Measure-
    ment (LC-MS: Rt/
    Ex. R1 cond. [M + H]+)
    334
    Figure US20140179670A1-20140626-C00811
         		9 0.76 535
    335
    Figure US20140179670A1-20140626-C00812
         		9 0.81 549
    336
    Figure US20140179670A1-20140626-C00813
         		9 0.84 563
    337
    Figure US20140179670A1-20140626-C00814
         		9 0.94 563
    338
    Figure US20140179670A1-20140626-C00815
         		9 0.78 564
    339
    Figure US20140179670A1-20140626-C00816
         		9 1.08 604
    340
    Figure US20140179670A1-20140626-C00817
         		9 0.75 521
    341
    Figure US20140179670A1-20140626-C00818
         		9 0.75 521
    342
    Figure US20140179670A1-20140626-C00819
         		9 0.73 535
    343
    Figure US20140179670A1-20140626-C00820
         		9 0.76 549
    344
    Figure US20140179670A1-20140626-C00821
         		9 0.76 564
    345
    Figure US20140179670A1-20140626-C00822
         		9 0.74 550
    346
    Figure US20140179670A1-20140626-C00823
         		9 0.98 589
    347
    Figure US20140179670A1-20140626-C00824
         		9 0.72 551
    348
    Figure US20140179670A1-20140626-C00825
         		9 0.76 564
    349
    Figure US20140179670A1-20140626-C00826
         		9 0.96 549
    350
    Figure US20140179670A1-20140626-C00827
         		9 0.96 549
  • TABLE 73
    351
    Figure US20140179670A1-20140626-C00828
         		9 0.72 536
    352
    Figure US20140179670A1-20140626-C00829
         		9 0.71 536
    353
    Figure US20140179670A1-20140626-C00830
         		9 1.11 706
    354
    Figure US20140179670A1-20140626-C00831
         		9 1.10 678
    355
    Figure US20140179670A1-20140626-C00832
         		9 0.95 607
    356
    Figure US20140179670A1-20140626-C00833
         		9 0.91 578
    357
    Figure US20140179670A1-20140626-C00834
         		9 0.86 606
    • Example 358
  • Figure US20140179670A1-20140626-C00835
  • To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (1.0 g) in acetonitrile (20 ml) was added Selectfluor (trade mark) (1.2 g) and the resulting mixture was stirred at 80° C. for four hours. To the reaction mixture was added 10% hydrochloric acid followed by an addition of ethyl acetate (20 ml×2) such the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile (238 mg). UPLC/MS 470 (M+H)/1.023 min. (measurement condition 9)
    • Example 359
  • The below-mentioned compound was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 358.
  • Figure US20140179670A1-20140626-C00836
  • UPLC/MS 581 (M+H)/0.98 min.
    • Example 360
  • Figure US20140179670A1-20140626-C00837
  • To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (205 mg) in acetonitrile (10 ml) were added lithium chloride (23 mg), ammonium hexanitrato cerate(IV) (498 mg) and acetic acid (2.5 ml) and the resulting mixture was stirred with heating under reflux for five hours. To the reaction mixture was 10% aqueous sodium thiosulfate solution (10 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-chloro-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (238 mg). UPLC/MS 486 (M+H)/1.13 min (measurement condition 9)
  • The compounds indicated in the below-mentioned table (Example 361-362) was obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 360.
  • Figure US20140179670A1-20140626-C00838
  • TABLE 74
    Measurement
    Ex. R1 cond. (LC-MS: Rt/[M + H]+)
    361
    Figure US20140179670A1-20140626-C00839
         		9 0.953 543
    362
    Figure US20140179670A1-20140626-C00840
         		9 0.791 557
    • Example 363
  • The below-mentioned compound was obtained by using the iodide product prepared in Example 101 according to the similar reaction and treatment method to those described in Example 123.
  • Figure US20140179670A1-20140626-C00841
  • 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carbonitrile
  • UPLC/MS 477 (M+H)/0.990 min. (measurement condition 9)
    • Example 364-367
  • Figure US20140179670A1-20140626-C00842
    Figure US20140179670A1-20140626-C00843
    • Step 1 Example 364
  • The iodide product was obtained by using the compound prepared in Example 319 according to the similar reaction and treatment method to those described in Example 101. UPLC/MS 767 (M+H)/1.20 min (measurement condition 9)
    • Step 2 Example 365
  • The cyano product was obtained by using the compound prepared in Example 364 according to the similar reaction and treatment method to those described in Example 363. UPLC/MS 666 (M+H)/1.128 min (measurement condition 9)
    • Step 3 Example 366
  • The de CBZ product was obtained by using the compound prepared in Example 365 according to the similar reaction and treatment method to those described in Example 329. UPLC/MS 533 (M+H)/0.71 min (measurement condition 9)
    • Step 4 Example 367
  • The methylated product was obtained by using the compound prepared in Example 366 according to the similar reaction and treatment method to those described in Example 69. UPLC/MS 546 (M+H)/1.09 min (measurement condition 9)
    • Examples 368-370
  • Figure US20140179670A1-20140626-C00844
    • Step 1 Example 368
  • The iodide product was obtained by using the compound of Example 327 according to the similar reaction and treatment method to those described in Example 101. UPLC/MS 610 (M+H)/1.11 min (measurement condition 9)
    • Step 2 Example 369
  • The carboxylic product was obtained by using the compound prepared in Example 369 according to the similar reaction and treatment method to those described in Example 132. UPLC/MS 528 (M+H)/0.90 min (measurement condition 9)
    • Step 3 Example 370
  • The amide product was obtained by using the compound prepared in Example 369 according to the similar reaction and treatment method to those described in Example 142. UPLC/MS 527 (M+H)/0.86 min (measurement condition 9). Melting point: 261° C.
    • Examples 371-372
  • Figure US20140179670A1-20140626-C00845
    • Step 1 Example 371
  • The sulfonic acid product was obtained by using the compound prepared in Example 334 according to the similar reaction and treatment method to those described in Example 191. UPLC/MS 614 (M+H)/0.708 min (measurement condition 9)
    • Step 2 Example 372
  • The sulfonamide product was obtained by using the compound prepared in Example 371 according to the similar reaction and treatment method to those described in Example 205. UPLC/MS 615 (M+H)/0.672 min (measurement condition 9)
    • Example 373
  • Figure US20140179670A1-20140626-C00846
  • To a solution of the compound prepared in Example 111 (300 mg) in chloroform (4.0 ml) were added at room temperature 2,2,6,6-tetramethylpiperidine 1-oxyl (78 mg) and iodobenzene diacetate (322 mg), and the resulting mixture was stirred at room temperature for six hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(6-methyl-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (260 mg). UPLC/MS 494 (M+H)/1.016 min (measurement condition 9)
    • Example 374
  • Figure US20140179670A1-20140626-C00847
  • A solution of the compound prepared in Example 111 (200 mg), tosyl chloride (190 mg), N-methylimidazole (80 μl) and triethylamine (140 μl) in toluene (6.0 ml) was stirred at 25° C. for three hours. To the reaction solution was added water (20 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To the residue were then added sodium methanthiolate (2.0 g, 15% aqueous solution), N,N-dimethy formamide (3 ml) and the resulting mixture was stirred at 25° C. for three hours. To the reaction solution was added water (20 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(6-methyl-3-(1-(methylthio)propane-2-yl)-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (115 mg).
  • UPLC/MS 526 (M+H)/1.094 min (measurement condition 9)
    • Example 375
  • Figure US20140179670A1-20140626-C00848
  • To a solution of the compound prepared in Example 374 (115 mg) in acetic acid (2.0 ml) was added at 25° C. sodium tungstate(VI) dihydrate (5.0 mg), aqueous hydrogen peroxide solution (110 mg, 31% aqueous solution) and the resulting mixture was stirred at the same temperature for four hours. To the reaction solution was added aqueous sodium hydrogen sulfite solution and the resulting mixture was stirred at 25° C. for one hour. To the reaction solution was added ethyl acetate (10 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(6-methyl-3-(methanesulfonyl)propane-2-yl)-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (108 mg). UPLC/MS 558 (M+H)/0.963 min
    • Example 376
  • Figure US20140179670A1-20140626-C00849
  • To a solution of the compound prepared in Example 111 (1.58 g) in chloroform (25 ml) were added 2,2,6,6-tetramethylpiperidine-1-oxyl (598 mg) and diacetoxy iodobenzene (2.47 g) and the resulting mixture was stirred for fourteen hours. To the reaction solution were water (25 ml) and chloroform (25 ml) such that the intended products were extracted into an organic layer, and the organic layer was washed with water (25 ml×3), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted in hexane/ethyl acetate=1/1 (40 ml) and thereto was added 10% aqueous potassium carbonate solution (20 ml) such that the intended products were extracted into an aqueous layer. The aqueous layer was washed with hexane/ethyl acetate=1/1 (20 ml) and acidified with 20% aqueous citric solution and thereto added ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford (R)-2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propionic acid (749 mg).
  • UPLC/MS 510 (M+H)/0.94 min (measurement condition 9)
    • Examples 377-384
  • The compounds indicated in the below-mentioned table (Examples 377-384) were obtained by using the carboxylic product prepared in Example 376 according to the similar reaction and treatment method to those described in Example 142.
  • Figure US20140179670A1-20140626-C00850
  • TABLE 75
    Measure-
    ment (LC-MS: Rt/
    Ex. R1 m.p. cond. [M + H]+)
    377 NH2 226 9 0.88 509
    378 NHMe 188 9 0.91 523
    379 NMe2 9 0.93 537
    380
    Figure US20140179670A1-20140626-C00851
         		9 0.93 567
    381
    Figure US20140179670A1-20140626-C00852
         		9 0.73 592
    382
    Figure US20140179670A1-20140626-C00853
         		9 0.94 563
    383
    Figure US20140179670A1-20140626-C00854
         		9 0.86 565
    384
    Figure US20140179670A1-20140626-C00855
         		9 0.94 579
    • Examples 385-393
  • The compounds indicated in the below-mentioned table (Examples 385-393) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 69.
  • Figure US20140179670A1-20140626-C00856
  • TABLE 76
    Measure-
    ment (LC-MS: Rt/
    Ex. R1 cond. [M + H]+)
    385 NMe2 9 0.74  524
    386
    Figure US20140179670A1-20140626-C00857
         		9 0.76  565
    387
    Figure US20140179670A1-20140626-C00858
         		9 0.763 641
    388
    Figure US20140179670A1-20140626-C00859
         		9 0.841 642
    389
    Figure US20140179670A1-20140626-C00860
         		9 0.992 613
    390
    Figure US20140179670A1-20140626-C00861
         		9 0.716 551
    391
    Figure US20140179670A1-20140626-C00862
         		9 0.746 566
    392
    Figure US20140179670A1-20140626-C00863
         		9 0.795 564
    393
    Figure US20140179670A1-20140626-C00864
         		9 1.06  573
    • Examples 394-396
  • Figure US20140179670A1-20140626-C00865
    • Step 1 Example 394
  • The bromo product was obtained by using the compound prepared in Example 376 according to the similar reaction and treatment method to those described in Example 93. UPLC/MS 590 (M+H)/1.023 min (measurement condition 9)
    • Step 2 Example 395
  • The methylated product was obtained by using the compound prepared in Example 394 according to the similar reaction and treatment method described in Example 108. UPLC/MS 524 (M+H)/0.804 min (measurement condition 9)
    • Step 31 Example 396
  • The amide product was obtained by using the compound prepared in Example 395 according to the similar reaction and treatment method to those described in Example 142. UPLC/MS 523 (M+H)/0.906 min (measurement condition 9)
    • Example 397
  • Figure US20140179670A1-20140626-C00866
  • To (methoxymethyl)triphenylphoshonium chloride (1.74 g) and tertiary-butoxy potassium (853 mg) was added at 0° C. glyme/toluene (10 ml/10 ml) and the resulting mixture was stirred for fifteen minutes. To the reaction mixture was added at 0° C. (R)-4-(5-(6-methyl-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 373) (500 mg) and the resulting mixture was stirred at room temperature for fifteen hours. To the reaction mixture was added water (20 ml) followed by an addition of ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(4-methoxy-3-buten-2-yl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (350 mg). UPLC/MS 522 (M+H)/1.00 min. (measurement condition 9)
    • Example 398
  • Figure US20140179670A1-20140626-C00867
  • To a solution of (R)-4-(5-(3-(4-methoxy-3-buten-2-yl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 397) (300 mg) in tetrahydrofuran (3.0 ml) was added 1N hydrochloric acid (10 ml) and the resulting mixture was stirred at 50° C. for two hours. To the reaction mixture was added water (10 ml) followed by an addition of ethyl acetate (20 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(6-methyl-2,4-dioxo-3-(4-oxobutane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (309 mg). UPLC/MS 508 (M+H)/1.06 min (measurement condition 9)
    • Examples 399-408
  • Figure US20140179670A1-20140626-C00868
  • The compounds indicated in the below-mentioned table (Examples 399-408) were obtained by using the compound prepared in Example 398 according to the similar reaction and treatment method to those described in Example 69.
  • TABLE 77
    Measurement (LC-MS: Rt/
    Ex. R1 cond. [M + H]+)
    399
    Figure US20140179670A1-20140626-C00869
         		9 0.807 579
    400
    Figure US20140179670A1-20140626-C00870
         		9 0.807 537
    401 NH2 9 0.894 523
    402
    Figure US20140179670A1-20140626-C00871
         		9 0.922 537
    403
    Figure US20140179670A1-20140626-C00872
         		9 0.897 551
    404
    Figure US20140179670A1-20140626-C00873
         		9 0.851 578
    405
    Figure US20140179670A1-20140626-C00874
         		9 0.791 593
    406
    Figure US20140179670A1-20140626-C00875
         		9 0.794 599
    407
    Figure US20140179670A1-20140626-C00876
         		9 0.896 591
    408
    Figure US20140179670A1-20140626-C00877
         		9 0.778 586
    • Example 409
  • Figure US20140179670A1-20140626-C00878
  • The compound prepared in Reference Example 248 was suspended in propanenitrile (30 ml) and thereto were added 4-cyanobenzohydrazide (383 mg), silver trifluoroacetate (263 mg) and trimethylsilyl triflate (0.23 ml) and the resulting mixture was stirred for two hours with heating under reflux. The mixture was cooled to 0° C. and thereto were then added ethyl acetate (50 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated saline (10 ml) and the precipitates were separated by filtration. The filtrates were concentrated under reduced pressure and thereto was then added ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol). The intended product obtained was recrystallized from ethyl acetate/hexane to afford 5-(4-cyanophenyl)-4-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazole-3-carboxamide (99 mg).
  • 1H-NMR (MeOH-d4: 400 MHz) δ: 1.17 (t, 1.5H, J=7.1 Hz), 1.19 (t, 1.5H, J=7.0 Hz), 1.64 (s, 1.5H), 1.66 (s, 1.5H), 3.94-4.05-(m, 2H), 7.55-7.57 (m, 0.5H), 7.70-7.78 (m, 2H), 7.81-7.88 (m, 3H), 7.90-7.95 (m, 2.5H).
  • UPLC/MS 510 (M+H)/0.85 min (measurement condition 9), melting point: 256° C.
    • Examples 410-417
  • The compounds indicated in the below-mentioned table (Examples 410-417) were obtained by using the corresponding starting materials according to the similar reaction and treatment method to those described in Example 409.
  • Figure US20140179670A1-20140626-C00879
  • TABLE 78
    Measurement
    Ex. R3 R1 R4 cond. (LC-MS: Rt/[M + H]+)
    410
    Figure US20140179670A1-20140626-C00880
         		Et H 9 538 0.897
    411
    Figure US20140179670A1-20140626-C00881
         		Et H 9 581 1.039
    412
    Figure US20140179670A1-20140626-C00882
         		Et H 9 564 0.738
    413
    Figure US20140179670A1-20140626-C00883
         		Et H 9 525 0.950
    414
    Figure US20140179670A1-20140626-C00884
         		Et F 9 544 0.913
    415 H
    Figure US20140179670A1-20140626-C00885
         		H 9 559 0.831
    416 Me
    Figure US20140179670A1-20140626-C00886
         		H 9 573 0.865
    417 Me i-Pr F 9 513 0.954
    • Examples 418-422
  • Figure US20140179670A1-20140626-C00887
    • Step 1 Example 418
  • The carboxylic acid product was obtained by using the compound prepared in Example 411 according to the similar reaction and treatment method to those described in Example 85. UPLC/MS 525 (M+H)/0.831 min (measurement condition 9)
    • Step 2
  • The compounds indicated in the below-mentioned table (Examples 419-422) were obtained by using the carboxylic acid product prepared in Example 418 according to the similar reaction and treatment method to those described in Example 142.
  • TABLE 79
    Measurement
    Ex. R cond. (LC-MS: Rt/[M + H]+)
    419 NMe2 9 552 (M + H)/0.890 (min)
    420 NHMe 9 538 (M + H)/0.860 (min)
    421 NH2 9 524 (M + H)/0.824 (min)
    422
    Figure US20140179670A1-20140626-C00888
         		9 594 (M + H)/0.902 (min)
    • Examples 423-425
  • Figure US20140179670A1-20140626-C00889
    • Step 1 Example 423
  • To a solution of the compound prepared in Example 1 (3.0 g) in DMF (30 ml) were added potassium hexamethyldisilazide (KHMDS) (2.65 g) and methyl iodide (0.8 ml) and the resulting mixture was stirred at room temperature for thirty minutes. To the reaction mixture was added 10% aqueous citric acid solution (30 ml) followed by an addition of ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the ethyl product (2.1 g). UPLC/MS 466 (M+H)/1.010 min (measurement condition 9)
    • Step 2 Example 424
  • The sulfonic acid product (498 mg) was obtained by using the compound prepared in Example 423 (500 mg) according to the similar reaction and treatment method to those described in Example 191. UPLC/MS 546 (M+H)/0.748 min (measurement condition 9)
    • Step 3 Example 425
  • The sulfonamide product (235 mg) was obtained by using the compound prepared in Example 424 (358 mg) according to the similar reaction and treatment method to those described in Example 209. UPLC/MS 546 (M+H)/0.937 min (measurement condition 9)
    • Example 426
  • Figure US20140179670A1-20140626-C00890
  • (−)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide was obtained by using the compound prepared in Example 199 according to the similar reaction and treatment method to those described in Example 209.
  • UPLC/MS 531 (M+H)/0.93 min. (measurement condition 9)
    • Examples 427-429
  • Figure US20140179670A1-20140626-C00891
    • Step 1 Example 427
  • The carboxylic acid (128 mg) was obtained by using the compound prepared in Example 398 according to the similar reaction and treatment method to those described in Example 376. UPLC/MS 524 (M+H)/0.952 min (measurement condition 9)
    • Step 2 Examples 428-429
  • The compounds indicated in the below-mentioned table (Examples 428-429) were obtained by using the compounds prepared in Example 427 according to the similar reaction and treatment method to those described in Example 142.
  • TABLE 80
    Measurement
    Ex. R cond. (LC-MS: Rt/[M + H]+)
    428 NH2 9 523 (M + H)/0.894 (min)
    429 NHMe 9 537 (M + H)/0.922 (min)
    • Test Example 1 Inhibitory Action Against Human Neutrophil Elastase
  • Hereinafter, the pharmacological test result on the representative compound of the present invention was shown, but the present invention should not be limited to the results of these testing examples.
  • Assay buffer (0.4 unit/ml HNE (human neutrophil elastase, available from Elastin Products Company), 200 mM HEPES [N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)], pH 7.5, 2M NaCl, 0.002% Brij-35) 100 μl, water for injection 40 μl and DMSO (dimethyl sulfoxide) solution of the present compound 20 μl were mixed in a 96 well plate and the mixed solutions were pre-incubated at 37° C. for five minutes. After pre-incubation, MeOSuc-AAPV-AMC (methoxysuccinyl-alanyl-alanyl-prolyl-valyl-aminomethyl cumaride (available from Sigma Aldrich Co.) solution as fluorogenic substrate (which was dissolved in 10% DMSO solution so as to adjust to 0.5 mM) 40 μl was added to the above-prepared mixed solution so as to initiate the reaction, and the mixture was incubated at 37° C. for five minutes. The fluorescence intensity of AMC was measured at an excitation wavelength of 380 nM and a fluorescence wavelength of 460 nm and the inhibition ratio was determined.
  • With respect to the compounds of Examples, IC50 value (μM) (which means the compound concentration required for 50% inhibition of human neutrophil elastase) or inhibition ratio (%) at 100 μM is shown in the below-mentioned table.
  • TABLE 81
    IC50 value
    (μM) or
    Inhibition ratio
    Ex. (%)
    1 0.019 μM
    2 0.035 μM
    3 0.104 μM
    4 0.131 μM
    5 0.170 μM
    6 0.123 μM
    7 0.120 μM
    8 0.064 μM
    9  2.95 μM
    10 0.648 μM
    11  1.36 μM
    12  1.49 μM
    13 0.086 μM
    14  12.6 μM
    15 76%
    16 90%
    17 0.095 μM
    18 0.047 μM
    19  1.84 μM
    20 83%
    21 0.252 μM
    22 0.793 μM
    23 0.651 μM
    28  2.24 μM
    29  2.14 μM
    30 0.064 μM
    31 0.019 μM
    32 50%
    33  74.6 μM
    34 0.232 μM
    35 49%
    36 0.111 μM
    37 0.191 μM
    38  7.91 μM
    39  19.9 μM
    40  8.34 μM
    57 0.159 μM
    58 0.552 μM
    60 0.076 μM
    61 0.074 μM
    62 0.068 μM
    68 0.111 μM
    69 0.114 μM
    70 0.043 μM
    71 0.169 μM
    72 0.138 μM
    73 0.535 μM
    74 0.312 μM
    75 0.656 μM
    76 0.232 μM
    77 0.184 μM
    80  1.29 μM
    81 0.616 μM
    82 0.108 μM
    83 0.776 μM
    84 0.147 μM
    85 0.0043 μM 
    86 0.0032 μM 
    102 0.150 μM
    103  12.2 μM
    104  92.5 μM
    105  22.3 μM
    106  13.9 μM
    107  5.40 μM
    108 0.332 μM
    • Test Example 2 Inhibitory Action 2 Against Human Neutrophil Elastase
  • Hereinafter, the pharmacological test result on the representative compound of the present invention was shown, but the present invention should not be limited to these testing examples.
  • Assay buffer (0.4 unit/ml HNE (human neutrophil elastase, available from Elastin Products Company), 200 mM HEPES [N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)], pH 7.5, 400 mM NaCl, 0.2 mg/ml BSA (bovine serum albumin)) 100 μl, water for injection 20 μl and 1% DMSO (dimethyl sulfoxide) solution of the present compound 20 μl were mixed in a 96 well plate and the mixed solutions were pre-incubated at 37° C. for five minutes. After pre-incubation, MeOSuc-AAPV-AMC (methoxysuccinyl-alanyl-alanyl-prolyl-valyl-aminomethyl cumaride (available from Sigma Aldrich Corp.) solution as fluorogenic substrate (which was dissolved in 10% DMSO solution so as to adjust to 0.5 mM) 40 μl was added to the above-prepared mixed solution so as to initiate the reaction, and the mixture was incubated at 37° C. for five minutes. The fluorescence intensity of AMC was measured at an excitation wavelength of 380 nM and a fluorescence wavelength of 460 nm and the inhibition ratio was determined.
  • With respect to the compounds of Examples, IC50 value (nM) (which means the compound concentration required for 50% inhibition of human neutrophil elastase) is shown in the below-mentioned table.
  • TABLE 82
    IC50 value
    Ex. (nM)
    1 16.9
    2 18.6
    17 23.4
    37 64.2
    41 12.6
    42 3.5
    50 13.7
    55 4.9
    65 5.5
    90 353.1
    143 6.9
    148 14.5
    151 6.0
    153 5.4
    156 10.0
    162 12.6
    173 7.9
    176 11.4
    178 13.5
    179 8.7
    183 363
    184 5.3
    187 19.4
    188 18.6
    191 23.1
    196 8.4
    205 15.0
    206 9.3
    207 13.5
    209 9.3
    211 8.8
    218 14.7
    220 21.7
    221 19.8
    227 7.8
    239 7.7
    242 14.3
    243 5.4
    249 11.9
    252 20.6
    255 9.2
    257 7.7
    261 7.2
    265 23.7
    267 11.6
    274 14.0
    276 12.0
    283 26.0
    285 24.3
    288 26.2
    293 25.1
    295 14.6
    297 29.7
    298 42.7
    300 14.3
    305 22.0
    306 41.0
    313 27.2
    315 24.2
    318 14.9
    324 9.6
    326 24.3
    328 24.8
    337 4.5
    339 7.3
    343 7.3
    351 7.4
    355 8.1
    357 10.2
    358 29.5
    359 15.3
    360 16.7
    361 6.3
    363 19.1
    367 14.0
    371 17.4
    375 12.3
    377 11.0
    379 18.7
    383 12.8
    386 10.1
    387 8.9
    390 10.4
    392 5.1
    393 26.3
    399 12.9
    404 14.2
    406 12.9
    408 14.7
    412 21.0
    413 22.3
    416 16.3
    417 39.8
    420 28.6
    422 14.5
    428 9.0
    • INDUSTRIAL APPLICABILITY
  • The present compound is useful as a prophylactic agent and/or a therapeutic agent for various diseases associated with elastase such as inflammatory disease. The diseases in which elastase is suggested to associate with pathological conditions include, for example, chronic obstructive pulmonary disease (COPD), pulmonary cystic fibrosis, emphysema, adult respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic pulmonary fibrosis (IPF), chronic interstitial pneumonia, chronic bronchitis, chronic airway infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection of organ transplantation, premature rupture of membrane, bullosa, shock, sepsis, systemic lupus erythematodes (SLE), Crohn disease, disseminated intravascular coagulation (DIC), ischemia-reperfusion induced-tissue injury, corneal scar tissue formation, myelitis, lung squamous cell carcinoma, pulmonary adenocarcinoma, lung cancers such as non-small cell lung cancer, breast cancer, liver cancer, bladder cancer, colorectal cancer, skin cancer, pancreas cancer, glioma and the others. Thus, an agent showing inhibitory activity for elastase is useful for treatment or prophylaxis of diseases associated with elastase.

Claims (20)

1.-19. (canceled)
20. A compound represented by formula (I) or physiologically acceptable salts thereof:
Figure US20140179670A1-20140626-C00892
[wherein
R1 represents a hydrogen atom, a C1-10 alkyl group, a C2-6 alkene group or a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S,
said alkyl group and said alkene group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
Substituent List 1:
(1) hydroxy group,
(2) halogen atom,
(3) cyano group,
(4) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
hydroxy group,
halogen atom,
cyano group,
—C(═O)ORb,
—C(═O)NRcRd,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(5) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with hydroxy group,
halogen atom,
cyano group,
—C(═O)ORb,
—C(═O)NRcRd,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaC(═O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NR C(═O)Rb group, —NRaC(O)NRcRd group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(6) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be substituted at substitutable positions with
C1-3 alkyl group optionally substituted with hydroxy or halogen,
C1-3 alkoxy group optionally substituted with hydroxy or halogen,
hydroxy group,
halogen atom,
cyano group,
—NRaC(═O)Rb,
—NRaC(═O)NRcRd,
—NRaS(═O)mRb,
—C(═O)ORb,
—C(═O)NRcRd,
—S(═O)mNRcRd,
—S(═O)mRb or
—NRcRd),
(7) three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, cyano, —NRaC(═O)Rb, —NRaC(═O)NRcRd, —NRaS(═O)mRb, —C(═O)ORb, —C(═O)NRcRd or —NRcRd),
C1-3 alkoxy group optionally substituted with hydroxy or halogen,
hydroxy group,
halogen atom,
cyano group,
—NRaC(═O)Rb,
—NRaC(═O)NRcRd,
—NRaS(═O)mRb,
—C(═O)ORb,
—C(═O)NRcRd,
—C(═O)Rb,
—S(═O)mNRcRd,
—S(═O)mRb,
—NRcRd or
oxo group),
(8) —NRaRe group,
(9) —OC(═O)NRcRd group,
(10) —C(═O)Rf group,
(11) —S(═O)mRg group,
(12) thiol group,
(13) nitro group and
(14) —ORe group,
said three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group for R1 may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
Substituent List 2:
(1) hydroxy group,
(2) halogen atom,
(3) cyano group,
(4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
hydroxy group,
halogen atom,
cyano group,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
three- to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with
hydroxy group,
halogen atom,
cyano group,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or a —NRcRd group) or
three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(6) C1-6 alkylthio group (said alkylthio group may be optionally substituted at substitutable positions with
hydroxy group,
halogen atom,
cyano group,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(7) five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with
C1-3 alkyl group optionally substituted with hydroxy or halogen,
C1-3 alkoxy group optionally substituted with hydroxy or halogen,
hydroxy group,
halogen atom,
cyano group,
—NRaC(═O)Rb,
—NRaS(═O)mRb,
—C(═O)ORb,
—C(═O)NRcRd,
—S(═O)mNRcRd,
—S(═O)mRb or
—NRcRd),
(8) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
C1-3 alkyl group optionally substituted with hydroxy or halogen,
C1-3 alkoxy group optionally substituted with hydroxy or halogen,
hydroxy group,
halogen atom,
cyano group,
—NRaC(═O)Rb,
—NRaS(═O)mRb,
—C(═O)ORb,
—C(═O)NRcRd,
—NRcRd or
oxo group),
(9) —NRaRe group,
(10) —OC(═O)NRcRd group,
(11) —C(═O)Rf group,
(12) —S(═O)mRg group,
(13) thiol group,
(14) oxo group,
(15) nitro group,
(16) —NRaC(═O)Rb group,
(17) —NRaC(═O)NRcRd group,
(18) —NRaS(═O)mRb group,
(19) —C(═O)ORb group and
(20) —C(═O)NRcRd group,
R2 represents a hydrogen atom, a halogen atom, a cyano group, a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)R),
Ar1 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
L represents a six membered unsubstituted aromatic ring group optionally containing 1 to 2 nitrogen atoms, a Pyr-1 group of the following formula or a Tri-1 group of the following formula:
Figure US20140179670A1-20140626-C00893
(in each formula,
the bond 1 represents a binding to uracil ring, the bond 2 represents a binding to Ar2, and the Z1 and Z2 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —CHO group, a nitro group, a hydroxy group, a —NRcRd group, a —NRaC(═O)Rh group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a —S—Rg3 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted with hydroxy, halogen, C1-6 alkyl, C1-3 alkoxy, —C(═O)ORa, —C(═O)Ra or —NRaRb), a C1-6 alkyl group or an C2-6 alkene group (said alkyl group and said alkene group may independently of each other be optionally substituted with halogen, hydroxy, —NRcRd, —C(═O)NRcRd, —NRaS(O)mRh, —C(═O)NRcRd or —C(═O)ORa),
Ar2 represents a five to six-membered aromatic ring group optionally containing one to three heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group is substituted at one or more substitutable positions with C1-6 alkyl group optionally substituted with hydroxy, cyano or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —NRaC(═O)Rh group, —NRaS(═O)mRh group, —NRaC(═O)NRcRd group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)mNRcRd group, —S(═O)nRh group or —NRcRd group),
Ra represents a hydrogen atom or a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen),
Rb represents a hydrogen atom, a C1-6 alkyl group optionally substituted with hydroxy or halogen, a benzyl group optionally substituted with methoxy or nitro, or a C3-6 cycloalkyl group optionally substituted with hydroxy or halogen,
Rb2 represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb or halogen), a benzyl group (said benzyl group may be optionally substituted with methoxy or nitro) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen),
Rb3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen),
Rb4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with halogen), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or halogen), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or halogen) or an 2-isopropyl-5-methylcyclohexyl,
Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group optionally substituted with C1-3 alkoxy, cyano, hydroxy or halogen, or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb, —NRaC(═O)ORh or —NRaC(═O)Rh), C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, halogen atom or oxo group),
Rc2 and Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or halogen atom), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated or unsaturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group, C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORh group, —NRaC(═O)Rh group, —C(═O)ORa group, hydroxy group, halogen atom or oxo group),
Re represents
a hydrogen atom,
a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
an -A group,
a —C(═O)-A group,
a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
a C1-6 alkoxycarbonyl group (the alkyl moiety of said alkoxycarbonyl group may be optionally substituted with hydroxy or halogen),
a —C(═O)NRcRd group or
a —S(═O)mRb group,
Rf represents
a hydrogen atom,
a hydroxy group,
a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
a C1-3 alkoxy group (said alkoxy group may be optionally substituted with phenyl group optionally substituted with methoxy or nitro, hydroxy group, cyano group, halogen atom, C1-3 alkoxy group or —NRcRd group),
an -A group or
a —NRaRi group,
Rg represents
a hydroxy group,
a chlorine atom,
a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd),
an -A group or
a —NRaRi group,
Rg2 represents
a hydroxy group,
a chlorine atom,
a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or —NRcRd) or
an -A group,
Rg3 represents
a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy or NRcRd) or
an -A group,
Rh represents a C1-6 alkyl optionally substituted with hydroxy or halogen,
Ri represents
a hydrogen atom,
a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, cyano, halogen, C1-3 alkoxy, C3-6 cycloalkyl or —NRcRd),
an -A group,
a —C(═O)Rh group,
a —C(═O)A group or
a C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy, halogen, cyano, C1-3 alkoxy or —NRcRd),
A represents
a five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group or —NRcRd group),
a three to six-membered saturated- or four to six-membered unsaturated-aliphatic ring group each optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —C(═O)OH group, —NRcRd group or oxo group),
m represents an integer of 1 or 2 and
n represents an integer of 0 to 2].
21. The compound according to claim 20 or physiologically acceptable salts thereof, wherein
Z1 and Z2 represent independently of each other a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —CHO group, a nitro group, a —NRaC(═O)Rb group, a hydrogen atom, a —S(═O)mNRc2Rd2 group, a —S(═O)mNRaC(═O)Rb3 group, a —S(═O)mNRaC(═O)ORb4 group, a —S(═O)mNRaC(═O)NRaRb3 group, a —S(═O)mRg2 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said saturated aliphatic ring group may be optionally substituted with halogen, C1-6 alkyl, —C(═O)ORa or —C(═O)Ra) or a C1-6 alkyl group (said alkyl group may be optionally substituted with halogen, —C(═O)NRcRd, —NRaS(═O)mRh, —C(═O)NRcRd or —C(═O)ORb).
22. The compound according to claim 20 or 21 or physiologically acceptable salts thereof wherein
Ar1 represents a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group), and
Ar2 represent a benzene ring or a pyridine ring (said benzene ring and said pyridine ring are substituted independently of each other at one to three substitutable positions with C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group).
23. The compound according to claim 20 or
physiologically acceptable salts thereof wherein
Ar1 represents the following formula of Ar1-1:
Figure US20140179670A1-20140626-C00894
(in the formula, K1, K2, K3 and K4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and X represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)R1 group, a —S(═O)nRh group or a —NRcRd group,
said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of K1 to K4 with further C1-6 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group),
Ar2 represents the following formula Ar2-1:
Figure US20140179670A1-20140626-C00895
(in the formula, L1, L2, L3 and L4 represent all carbon atoms for benzene ring, or only one nitrogen atom and the remaining carbon atoms for pyridine ring, and Y represents a C1-6 alkyl group optionally substituted with hydroxy or halogen, a C1-3 alkoxy group optionally substituted with hydroxy or halogen, a hydroxy group, a halogen atom, a cyano group, a nitro group, a —C(═O)NRcRd group, a —C(═O)ORa group, a —C(═O)Ra group, a —S(═O)nRh group or a —NRcRd group,
said benzene ring and said pyridine ring may be optionally substituted at one to two substitutable positions of L1 to L4 with further C4 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —C(═O)NRcRd group, —C(═O)ORa group, —C(═O)Ra group, —S(═O)nRh group or —NRcRd group).
24. The compound according to claim 20 or physiologically acceptable salts thereof wherein R2 represents a —NRcRd group, a —N═CHN(CH3)2 group or a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, halogen, —NRcRd, —ORa or —OC(═O)Ra).
25. The compound according to claim 20 or physiologically acceptable salts thereof, wherein
Ra represents a hydrogen atom or a C1-6 alkyl group optionally substituted with hydroxy or halogen,
Rb represents a C1-6 alkyl group optionally substituted with hydroxy or halogen,
Rb2 represents a hydrogen atom, a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb or fluorine) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine),
Rb3 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine or chlorine), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine) or a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine),
Rb4 represents a hydrogen atom, a phenyl group (said phenyl group may be optionally substituted with fluorine or chlorine), a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), a C3-6 cycloalkyl group (said cycloalkyl group may be optionally substituted with hydroxy or fluorine) or an 2-isopropyl-5-methylcyclohexyl,
Rc and Rd represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with C1-3 alkoxy, cyano, hydroxy or fluorine), or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, —NRaRb, —NRaC(═O)ORh or —NRaC(═O)Rh), C1-3 alkoxy group, —NRaRb group, —NRaC(═O)ORa group, —NRaC(═O)Ra group, —C(═O)ORa group, hydroxy group, fluorine atom or oxo group),
Rc2 an Rd2 represent independently of each other a hydrogen atom or a C1-3 alkyl group (said alkyl group may be optionally substituted with phenyl group optionally substituted with methoxy, —NRaRb group, —NRa(C═O)ORh group, —NRaC(═O)Rh group, C1-3 alkoxy group, cyano group, hydroxy group or fluorine atom), or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group (said aliphatic ring group may be optionally substituted at substitutable positions with C1-6 alkyl, C1-3 alkoxy, —NRaRb, —NR C(═O)ORh, —NRaC(═O)Rh, —C(═O)ORa, hydroxy, fluorine or oxo),
Re represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), an -A group, an C1-6 alkylcarbonyl group (the alkyl moiety of said alkylcarbonyl group may be optionally substituted with hydroxy or fluorine) or a —S(═O)2Rb group,
Rf represents a hydroxy group, an -A group or an —NRaRi group,
Rg represents a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy, fluorine or —NRcRd), a chlorine atom, an -A group or a —NRaRi group,
Rg2 represents a hydroxy group, a C1-3 alkyl group (said alkyl group may be optionally substituted with hydroxy or fluorine), a chlorine atom or an -A group,
Rg3 represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, fluorine or —NRcRd),
Rh represents a C1-3 alkyl group optionally substituted with hydroxy or fluorine,
Ri represents a C1-6 alkyl group (said alkyl group may be optionally substituted with hydroxy, C1-3 alkoxy or fluorine) or an -A group,
A represents
an aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl (said aromatic ring group may be optionally substituted at substitutable positions with hydroxy or fluorine) or
an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl, C1-3 alkoxy, hydroxy, fluorine, —NRcRd or oxo), and
m represents an integer of 1 or 2.
26. The compound according to claim 20 or physiologically acceptable salts thereof wherein
R1 represents a C1-10 alkyl group (said alkyl group may be substituted at substitutable positions with one to three substituents selected from the group consisting of
Substituent List 8:
(1) hydroxy group,
(2) halogen atom,
(3) cyano group,
(7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with
C1-3 alkyl group optionally substituted with hydroxy or halogen,
C1-3 alkoxy group optionally substituted with hydroxy or halogen,
hydroxy group,
halogen atom,
cyano group,
—NRaC(═O)Rb,
—NRaS(═O)mRb,
—C(═O)ORb,
—C(═O)NRcRd,
—C(═O)Rb,
—NRcRd or
oxo group),
(8) —NRaRe group,
(10) —C(═O)Rf group,
(11) —S(═O)mRg group, and
(12) thiol group,
or
a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
Substituent List 9:
(1) hydroxy group,
(2) halogen atom,
(3) cyano group,
(4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with
hydroxy group,
halogen atom,
cyano group,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NR C(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or —NRcRd group) or
three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(5) C1-6 alkoxy group (said alkoxy group may be optionally substituted at substitutable positions with hydroxy group,
halogen atom,
cyano group,
five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S (said aromatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —S(═O)mNRcRd group, —S(═O)mRb group or a —NRcRd group) or
three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —NRaC(═O)Rb group, —NRaS(═O)mRb group, —C(═O)ORb group, —C(═O)NRcRd group, —NRcRd group or oxo group),
(11) —C(═O)Rf group,
(12) —S(═O)mRg group, and
(14) oxo group.
27. The compound according to claim 20 or physiologically acceptable salts thereof wherein
R1 represents
a C1-10 alkyl group (said alkyl group may be substituted at substitutable positions with one to three substituents selected from the group consisting of
Substituent List 10:
(1) hydroxy group,
(2) halogen atom,
(7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S (said aliphatic ring group may be optionally substituted at substitutable positions with C1-3 alkyl group optionally substituted with hydroxy or halogen, C1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy, halogen, —C(═O)ORb, —C(O)NRcRd, —C(═O)Rb or oxo group),
(8) —NRaRe group, and
(11) —S(═O)2Rg group)
or
a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O (said aliphatic ring group may be optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of
Substituent List 11:
(1) hydroxy group,
(2) halogen atom,
(4) C1-6 alkyl group (said alkyl group may be optionally substituted at substitutable positions with hydroxy or halogen),
(9) —NRaRe group,
(11) —C(═O)Rf group and
(14) oxo group.
28. The compound according to claim 20 or physiologically acceptable salts thereof wherein L represents a Pyr-1 group.
29. The compound according to claim 20 or physiologically acceptable salts thereof wherein
the formula (I) represents the following formula (I′″):
Figure US20140179670A1-20140626-C00896
(wherein, Z1 represents a cyano group, a halogen atom, a —C(═O)NRcRd group, a —C(═O)ORb2 group, a hydrogen atom, a —S(═O)2NRc2Rd2 group, a —S(═O)2NRaC(═O)Rb3 group, a —S(═O)2NRaC(═O)ORb4 group, a —S(═O)2NRaC(═O)NRaRb3 group or a S(═O)2Rg group,
X represents a C1-3 alkyl group optionally substituted one or multiple fluorine atoms or a nitro group, and
Y represents a cyano group, a chlorine atom or a nitro group).
30. The compound according to claim 29 or physiologically acceptable salts thereof wherein
Z1 represents a —C(═O)NRcRd group, a —C(═O)ORb2 group, a —S(═O)2NRc2Rd2 group, a —S(═O)2NRa2C(═O)Rb3 group, a —S(═O)2NRaC(═O)ORb4 group, a —S(═O)2NRaC(═O)NRaRb3 group, a S(═O)2Rg group, an iodine atom, a bromine atom or a chlorine atom, and
R2 represents a C1-3 alkyl group optionally substituted with hydroxy.
31. The compound according to claim 20 selected from the following Group or physiologically acceptable salts thereof,
Group:
4-[5-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,
4-[5-[6-Methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,
4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
4-[5-[1-(3-Chlorophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,
4-(5-(3,6-Dimethyl-2,4-dioxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
4-(5-(6-Ethyl-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
(R)-4-(5-(3-(1-Hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
4-(4-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile,
(S)-4-(5-(2,4-Dioxo-3-(5-oxopyrrolidin-3-yl)1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
1-(4-Cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide,
4-(Dimethylamino)butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate,
(±)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,
(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,
(−)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,
(±)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
(−)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide.0.5 IPA solvates,
(±)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
(+)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,
N-(1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonyl)pivalamine,
Butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonylcarbamate,
N-(1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonyl)benzamide,
1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(ethylcarbonyl)-1H-pyrazole-4-sulfonamide,
(±)-4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,
(+)-4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,
(±)-4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,
4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzonitrile,
(R)-4-(5-(6-Methyl-2,4-dioxo-3-(pyrrolidin-3-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile,
4-(4-Chloro-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carbonitrile,
(R)-4-(5-(6-Methyl-3-(methanesulfonyl)propan-2-yl)-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,
(R)-2-(5-(1-(4-Cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonamide and
5-(4-Cyanophenyl)-4-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazole-3-carboxamide.
32. A pharmaceutical composition comprising the compound according to claim 20 or physiologically acceptable salts thereof as active ingredient and a pharmaceutical carrier.
33. An esterase inhibitor comprising the compound according to claim 20 or physiologically acceptable salts thereof as active ingredient.
34. An agent for treatment or prophylaxis of inflammatory diseases comprising the compound according to claim 20 or physiologically acceptable salts thereof.
35. An agent for treatment or prophylaxis of diseases required for elastase inhibitory activity comprising the compound according to claim 20 or physiologically acceptable salts thereof.
36. Use of the compound according to claim 20 or physiologically acceptable salts thereof in a preparation of medicine for treatment or prophylaxis of inflammatory diseases.
37. A pharmaceutical composition for use in treatment or prophylaxis of inflammatory diseases comprising the compound according to claim 20 or physiologically acceptable salts thereof as active ingredient.
38. A method for treatment or prophylaxis of inflammatory diseases which comprises administering a therapeutically effective amount of the compound according to claim 20 or physiologically acceptable salts thereof into a patient in need thereof.
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JP5799117B2 (en) * 2013-02-05 2015-10-21 大日本住友製薬株式会社 Pharmaceuticals consisting of uracil derivatives
US20140221335A1 (en) 2013-02-06 2014-08-07 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9115093B2 (en) 2013-03-04 2015-08-25 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
USRE47493E1 (en) 2014-02-20 2019-07-09 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9458113B2 (en) 2014-07-31 2016-10-04 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9475779B2 (en) 2014-07-31 2016-10-25 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9657015B2 (en) 2014-07-31 2017-05-23 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9440930B2 (en) 2014-07-31 2016-09-13 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9290457B2 (en) 2014-07-31 2016-03-22 Boehringer Ingelheim International Gmbh Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9409870B2 (en) 2014-12-15 2016-08-09 Chiesi Farmaceutici S.P.A. Compounds
AR108609A1 (en) 2016-05-31 2018-09-05 Chiesi Farm Spa DERIVATIVES OF IMIDAZOLONA AND PIRAZOLONA AS INHIBITORS OF THE ELASTASA DE HUMANA NEUTRÓFILOS (HNE)
EP3464268B1 (en) 2016-05-31 2020-03-11 Chiesi Farmaceutici S.p.A. Novel compounds
CN116410143A (en) * 2021-12-29 2023-07-11 杭州奥默医药股份有限公司 Polysubstituted uracil derivative, preparation method and application thereof
CN114436912B (en) * 2022-01-22 2023-04-18 浙江工业大学 Carbon-nitrogen axis chiral sulfonamide compound and synthesis method and application thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9702651D0 (en) * 1997-07-09 1997-07-09 Astra Pharma Prod Novel compounds
TW200500341A (en) 2002-11-12 2005-01-01 Astrazeneca Ab Novel compounds
SE0302487D0 (en) 2003-09-18 2003-09-18 Astrazeneca Ab Novel compounds
JP4973191B2 (en) 2004-11-10 2012-07-11 小野薬品工業株式会社 Nitrogen-containing heterocyclic compound and pharmaceutical use thereof
RU2008112691A (en) 2005-10-03 2009-10-10 Оно Фармасьютикал Ко., Лтд. (Jp) NITROGEN-CONTAINING HETEROCYCLIC COMPOUND AND ITS PHARMACEUTICAL APPLICATION
TW200808763A (en) 2006-05-08 2008-02-16 Astrazeneca Ab Novel compounds I
WO2009039127A1 (en) 2007-09-17 2009-03-26 Abbott Laboratories Uracil or thymine derivative for treating hepatitis c

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Bioorganic & Medicinal ChemistryVolume 11, Issue 23, 17 November 2003, Pages 4933-4940Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents. Yoshiaki et al., *

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